Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals

ABSTRACT

Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals  
     The invention relates to cycloalkyl derivatives having bioisosteric carboxylic acid groups and to their physiologically acceptable salts and physiologically functional derivatives.  
     What is described are compounds of the formula 1,  
                 
 
     in which the radicals are as defined, and their physiologically acceptable salts and processes for their preparations. The compounds are suitable for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders as well as of disorders in which insulin resistence is involved.

[0001] The invention relates to cycloalkyl derivatives havingbioisosteric carboxylic acid groups and to their physiologicallyacceptable salts and physiologically functional derivatives.

[0002] Compounds of a similar structure have already been described inthe prior art for the treatment of hyperlipidemia and diabetes (WO2000/64876).

[0003] The invention was based on the object of providing compoundswhich permit therapeutically utilizable modulation of lipid and/orcarbohydrate metabolism and are thus suitable for the prevention and/ortreatment of diseases such as type 2 diabetes and atherosclerosis andthe diverse sequelae thereof.

[0004] A series of compounds which modulate the activity of PPAreceptors has surprisingly been found. The compounds are suitable inparticular for activating PPARalpha and PPARgamma, it being possible forthe extent of the relative activation to vary depending on thecompounds.

[0005] Accordingly, the invention relates to compounds of the formula I

[0006] wherein

[0007] Ring A is (C₃-C₈)-cycloalkanediyl or (C₃-C₈)-cycloalkenediyl,wherein one or more of the carbon atoms of said (C₃-C₈)-cycloalkanediyland (C₃-C₈)-cycloalkenediyl groups are optionally replaced by an oxygenatom;

[0008] R₁, R₂ are each independently H, F, Br, CF₃, OCF₃, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, SCF₃, SF₅, OCF₂—CHF₂, O-phenyl, OH, or NO₂; or

[0009] R₁ and R₂, taken together with the carbon atoms of the phenylring to which they are attached, form a fused, unsaturated or completelyor partially saturated bicyclic (C₉-C₁₂)-aryl or (C₉-C₁₁)-heteroarylring system;

[0010] R3 is H, CF₃, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₃-C₈)-cycloalkylor phenyl;

[0011] x is (C₁-C₆)-alkanediyl, wherein one or more carbon atoms thereinis optionally replaced by an oxygen atom;

[0012] Y is (C₁-C₆)-alkanediyl or (C₁-C₆)-alkenediyl, wherein one ormore carbon atoms therein is optionally replaced by O, CO, S, SO or SO₂,and wherein said (C₁-C₆)-alkanediyl and (C₁-C₆)-alkenediyl groups areoptionally substituted by OH;

[0013] Ring B is a group selected from (a), (b) or (c):

[0014] (a) phenyl optionally mono- or disubstituted byNO_(2, Cl, CN,)(C₁-C₆)-alkyl or (C₁-C₆)-alkoxy

[0015] (b) tetrazole

[0016] (c) pyrrolidin-2-one wherein the pyrrolidinyl ring of saidpyrrolidin-2-one group contains an additional nitrogen atom or a sulfuratom and is substituted by oxo or thioxo, and is optionally substitutedon a nitrogen atom therein by R4;

[0017] R4 is (C₁-C₆)-alkyl, phenyl or benzyl;

[0018] and pharmaceutically acceptable salts thereof.

[0019] Preference is given to compounds of the formula I in which

[0020] Ring A is (C₃-C₈)-cycloalkanediyl or (C₃-C₈)-cycloalkenediyl,wherein one of the carbon atoms of said (C₃-C₈)-cycloalkanediyl and(C₃-C₈)-cycloalkenediyl groups is optionally replaced by an oxygen atom;

[0021] R1, R2 are each independently H, F, Br, CF₃, OCF₃, (C₁-C₆)-alkyl,O−(C₁-C₆)-alkyl, SCF₃, SF₅, OCF₂—CHF₂, O-phenyl, OH or NO₂; or

[0022] R₁, and R₂, taken together with the carbon atoms of the phenylring to which they are attached, form a fused, unsaturated or completelyor partially saturated bicyclic (C₉-C₁₂)-aryl or (C₉-C₁₁)-heteroarylring system;

[0023] R3 is H, CF₃, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl or phenyl;

[0024] X is (C₁-C₆)-alkanediyl, wherein one carbon atom therein isoptionally replaced by an oxygen atom;

[0025] Y is (C₁-C₆)-alkanediyl or (C₁-C₆)-alkenediyl, wherein one or twocarbon atoms of said (C₁-C₆)-alkanediyl and (C₁-C₆)-alkenediyl groupsare optionally replaced by O, CO, S, SO or SO_(2,) and wherein said(C₁-C₆)-alkanediyl and (C₁-C₆)-alkenediyl groups are optionallysubstituted by OH;

[0026] Ring B is a group selected from (a), (b) or (c):

[0027] (a) phenyl optionally mono- or disubstituted byNO_(2, Cl, CN,)(C₁-C₆)-alkyl or (C₁-C₆)-alkoxy

[0028] (b) tetrazole

[0029] (c) pyrrolidin-2-one wherein the pyrrolidinyl ring of saidpyrrolidin-2-one group contains an additional nitrogen atom or a sulfuratom in the 4-position and is substituted by oxo or thioxo in the5-position, and is optionally substituted on the nitrogen atom in the1-position by R4;

[0030] R4 is (C₁-C₆)-alkyl, phenyl or benzyl;

[0031] and pharmaceutically acceptable salts thereof.

[0032] Particular preference is given to compounds of the formula I inwhich

[0033] Ring A is (C₃-C₈)-cycloalkanediyl wherein one carbon atom thereinis replaced by an oxygen atom;

[0034] R₁, R₂ are each independently H, F, Br, CF₃, OCF₃, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, SCF₃, SF₅, OCF₂—CHF₂, O-phenyl, OH or NO₂; or

[0035] R₁ and R₂, taken together with the carbon atoms of the phenylring to which they are attached, form a fused, unsaturated or completelyor partially saturated bicyclic (C₉-C₁₂)-aryl or (C₉-C₁₁)-heteroarylring system;

[0036] R3 is H, CF₃, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl or phenyl;

[0037] X is (C₁-C₆)-alkanediyl, wherein the carbon atom in the1-position is replaced by an oxygen atom;

[0038] Y is (C₁-C₆)-alkanediyl or (C₁-C₆)-alkenediyl, wherein one or twocarbon atoms of said (C₁-C₆)-alkanediyl and (C₁-C₆)-alkenediyl groupsare optionally replaced by O, CO or SO₂, and wherein said(C₁-C₆)-alkanediyl and (C₁-C₆)-alkenediyl groups are optionallysubstituted by OH;

[0039] Ring B is a group selected from (a), (b) or (c):

[0040] (a) phenyl optionally mono- or disubstituted byNO_(2, Cl, CN,)(C₁-C₆)-alkyl or (C₁-C₆)-alkoxy

[0041] (b) tetrazole

[0042] (c) pyrrolidin-2-one wherein the pyrrolidinyl ring of saidpyrrolidin-2-one group contains an additional nitrogen atom or a sulfuratom in the 4-position and is substituted by oxo or thioxo in the5-position, and is optionally substituted on the nitrogen atom in the1-position by R4;

[0043] R4 is (C₁-C₆)-alkyl, phenyl or benzyl;

[0044] and pharmaceutically acceptable salts thereof.

[0045] Very particular preference is given to compounds of the formula Iin which

[0046] Ring A is cyclohexane-1,3-diyl; R₁, R₂ are each independently H,F, Br, CF₃, OCF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, SCF₃, SF₅, OCF₂—CHF₂,O-phenyl, OH or NO₂; or

[0047] R1 and R2, taken together with the carbon atoms of the phenylring to which they are attached, form a fused, unsaturated bicyclic(C₉-C₁₀)-aryl or (C₉-C₁₀)-heteroaryl ring system;

[0048] R3 is H, CF₃, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl or phenyl;

[0049] X is CH₂—O;

[0050] Y is (C₁-C₄)-alkanediyl, O—(C₁-C₄)-alkenediyl,(C₁-C₄)-alkenediyl, O—(C₁-C₄)-alkenediyl, O-—O₂ or O—CO, wherein said(C₁-C₄)-alkanediyl group is optionally substituted by OH;

[0051] Ring B is a group selected from (a), (b) or (c):

[0052] (a) phenyl optionally mono- or disubstituted byNO_(2, Cl, CN,)(C₁-C₆)-alkyl or (C₁-C₆)-alkoxy

[0053] (b) tetrazole

[0054] (c) thiazolidin-1,4-dione optionally substituted by R4 on thenitrogen in the 3-position-atom;

[0055] R4 is (C₁-C₆)-alkyl, phenyl or benzyl;

[0056] and pharmaceutically acceptable salts thereof.

[0057] Also preferred are compounds of the formula I in which

[0058] Ring A is cyclohexane-1,3-diyl;

[0059] R₁, R₂ are each independently H, F, Br, CF₃, (C₁-C₆)-alkyl orO—(C₁-C₆)-alkyl; or

[0060] R₁ and R₂, taken together with the carbon atoms of the phenylring to which they are attached, form naphthyl;

[0061] R3 is (C₁-C₆)-alkyl, (C₅-C₆)-cycloalkyl or phenyl;

[0062] X is CH₂—O;

[0063] Y is (C₁-C₄)-alkanediyl, O—(C₁-C₄)-alkanediyl,(C₁-C₄)-alkenediyl, O—(C₁-C₄)-alkenediyl, O—SO₂ or O—CO, where said(C₁-C₄)-alkanediyl group is optionally substituted by OH;

[0064] Ring B is a group selected from (a), (b) or (c):

[0065] (a) phenyl optionally mono- or disubstituted byNO_(2, Cl, CN,)(C₁-C₆)-alkyl or (C₁-C₆)-alkoxy

[0066] (b) tetrazole

[0067] (c) thiazolidin-2,4-dione optionally substituted by R4 on thenitrogen in the 3-position;

[0068] R4 is (C₁-C₆)-alkyl, phenyl or benzyl;

[0069] and pharmaceutically acceptable salts thereof.

[0070] Very particular preference is also given to the compounds of theformula I wherein:

[0071] Ring A is cyclohexane-1,3-diyl;

[0072] R2 is hydrogen;

[0073] X is CH₂—O—;

[0074] Y is —CH₂—CH₂—; and

[0075] Ring B is thiazolidine-2,4-dione.

[0076] Very particular preference is also given to the compounds of theformula I wherein:

[0077] R2 hydrogen and R1 is attached to the carbon of the phenyl ringthat is meta- or para- to the carbon by which the phenyl ring isattached to the oxazole ring.

[0078] This invention also encompasses all combinations of preferredaspects of the invention described herein.

[0079] The alkyl radicals in the substituents R1, R2, R3 and R4 may beeither straight-chain or branched.

[0080] Aryl means an aromatic carbocyclic mono- or bicyclic ring systemwhich comprises 6 to 10 atoms in the ring or rings.

[0081] Heteroaryl is a mono- or bicyclic aromatic ring system having 4to 11 ring members, in which at least one atom in the ring system is aheteroatom from the series N, O and S.

[0082] The compounds of the formula I comprise at least two centers ofasymmetry and may comprise more in addition. The compounds of theformula I may therefore exist in the form of their racemates, racemicmixtures, pure enantiomers, diastereomers and mixtures of diastereomers.The present invention encompasses all these isomeric forms of thecompounds of the formula I. These isomeric forms can be obtained byknown methods even if not specifically described in some cases.

[0083] Pharmaceutically acceptable salts are, because their solubilityin water is greater than that of the initial or basic compounds,particularly suitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts), andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

[0084] Salts with a pharmaceutically unacceptable anion such as, forexample, trifluoroacetate likewise belong within the framework of theinvention as useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

[0085] As used herein, the following definitions apply:

[0086] “Patient” means a warm blooded animal, such as for example rat,mice, dogs, cats, guinea pigs, and primates such as humans.

[0087] “Treat” or “treating” means to alleviate symptoms, eliminate thecausation of the symptoms either on a temporary or permanent basis, orto prevent or slow the appearance of symptoms of the named disorder orcondition.

[0088] “Therapeutically effective amount” means a quantity of thecompound which is effective in treating the named disorder or condition.

[0089] “Pharmaceutically acceptable carrier” is a non-toxic solvent,dispersant, excipient, adjuvant or other material which is mixed withthe active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient. One example of such a carrier is apharmaceutically acceptable oil typically used for parenteraladministration.

[0090] The term “physiologically functional derivative” used hereinrefers to any physiologically tolerated derivative of a compound of theformula I of the invention, for example an ester, which onadministration to a mammal such as, for example, a human is able to form(directly or indirectly) a compound of the formula I or an activemetabolite thereof.

[0091] Physiologically functional derivatives also include prodrugs ofthe compounds of the invention, as described, for example, in H. Okadaet al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can bemetabolized in vivo to a compound of the invention. These prodrugs maythemselves be active or not.

[0092] The compounds of the invention may also exist in variouspolymorphous forms, for example as amorphous and crystallinepolymorphous forms. All polymorphous forms of the compounds of theinvention belong within the framework of the invention and are a furtheraspect of the invention.

[0093] All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts,solvates and physiologically functional derivatives as described herein.

[0094] Use

[0095] This invention relates further to the use of compounds of theformula I and their pharmaceutical compositions as PPAR ligands. ThePPAR ligands of the invention are suitable as modulators of PPARactivity.

[0096] Peroxisome proliferator-activated receptors (PPAR) aretranscription factors which can be activated by ligands and belong tothe class of nuclear hormone receptors. There are three PPAR isoforms,PPARalpha, PPARgamma and PPARdelta, which are encoded by different genes(Peroxisome proliferator-activated receptor (PPAR): structure,mechanisms of activation and diverse functions: Motojima K, Cell StructFunct. October 1993; 18(5): 267-77).

[0097] Two variants of PPARgamma exist, PPARgamma₁ and gamma₂, which arethe result of alternative use of promoters and differential mRNAsplicing (Vidal-Puig et al. J. Clin. Invest., 97:2553-2561, 1996).Different PPARs have different tissue distribution and modulatedifferent physiological functions. The PPARs play a key role in variousaspects of the regulation of a large number of genes, the products ofwhich genes are directly or indirectly crucially involved in lipid andcarbohydrate metabolism. Thus, for example, PPARalpha receptors play animportant part in the regulation of fatty acid catabolism or lipoproteinmetabolism in the liver, while PPARgamma is crucially involved forexample in regulating adipose cell differentiation. In addition,however, PPARs are also involved in the regulation of many otherphysiological processes, including those which are not directlyconnected with carbohydrate or lipid metabolism. The activity ofdifferent PPARs can be modulated by various fatty acids, fatty acidderivatives and synthetic compounds to varying extents. For relevantreviews about functions, physiological effect and pathophysiology, see:Joel Berger et al., Annu. Rev. Med. 2002, 53, 409-435; Timothy Wilson etal. J. Med. Chem., 2000, Vol.43, No. 4, 527-550; Steven Kliewer et al.,Recent Prog Horm Res. 2001; 56: 239-63.

[0098] The present invention relates to compounds of the formula Isuitable for modulating the activity of PPARs, especially the activityof PPARalpha and PPARgamma. Depending on the modulation profile, thecompounds of the formula I are suitable for the treatment, control andprophylaxis of the indications described hereinafter, and for a numberof other pharmaceutical applications connected thereto (see, forexample, Joel Berger et al., Annu. Rev. Med. 2002, 53, 409-435; TimothyWilson et al. J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; StevenKliewer et al., Recent Prog Horm Res. 2001; 56: 239-63; Jean-CharlesFruchart, Bart Staels and Patrick Duriez: PPARS, Metabolic Disease andArteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52;2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARsin health and disease, NATURE, VOL 405, 25 MAY 2000; 421-4; Ines PinedaTorra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and BartStaels: Peroxisome proliferator-activated receptors: fromtranscriptional control to clinical practice, Curr Opin Lipidol 12:2001, 245-254).

[0099] Compounds of this type are particularly suitable for thetreatment and/or prevention of

[0100] 1.—disorders of fatty acid metabolism and glucose utilizationdisorders

[0101] disorders in which insulin resistance is involved

[0102] 2. Diabetes mellitus, especially type 2 diabetes, including theprevention of the sequelae associated therewith.

[0103] Particular aspects in this connection are

[0104] hyperglycemia,

[0105] improvement in insulin resistance,

[0106] improvement in glucose tolerance,

[0107] protection of the pancreatic β cells

[0108] prevention of macro- and microvascular disorders

[0109] 3. Dyslipidemias and their sequelae such as, for example,atherosclerosis, coronary heart disease, cerebrovascular disorders etc,especially those (but not restricted thereto) which are characterized byone or more of the following factors:

[0110] high plasma triglyceride concentrations, high postprandial plasmatriglyceride concentrations,

[0111] low HDL cholesterol concentrations

[0112] low ApoA lipoprotein concentrations

[0113] high LDL cholesterol concentrations

[0114] small dense LDL cholesterol particles

[0115] high ApoB lipoprotein concentrations

[0116] 4. Various other conditions which may be associated with themetabolic syndrome, such as:

[0117] obesity (excess weight), including central obesity

[0118] thromboses, hypercoagulable and prothrombotic states (arterialand venous)

[0119] high blood pressure

[0120] heart failure such as, for example (but not restricted thereto),following myocardial infarction, hypertensive heart disease orcardiomyopathy

[0121] 5. Other disorders or conditions in which inflammatory reactionsor cell differentiation may for example be involved are:

[0122] atherosclerosis such as, for example (but not restrictedthereto), coronary sclerosis including angina pectoris or myocardialinfarction, stroke

[0123] vascular restenosis or reocclusion

[0124] chronic inflammatory bowel diseases such as, for example, Crohn'sdisease and ulcerative colitis

[0125] pancreatitis

[0126] other inflammatory states

[0127] retinopathy

[0128] adipose cell tumors

[0129] lipomatous carcinomas such as, for example, liposarcomas

[0130] solid tumors and neoplasms such as, for example (but notrestricted thereto), carcinomas of the gastrointestinal tract, of theliver, of the biliary tract and of the pancreas, endocrine tumors,carcinomas of the lungs, of the kidneys and the urinary tract, of thegenital tract, prostate carcinomas etc

[0131] acute and chronic myeloproliferative disorders and lymphomas

[0132] angiogenesis

[0133] neurodegenerative disorders

[0134] Alzheimer's disease

[0135] multiple sclerosis

[0136] Parkinson's disease

[0137] erythemato-squamous dermatoses such as, for example, psoriasis

[0138] acne vulgaris

[0139] other skin disorders and dermatological conditions which aremodulated by PPAR

[0140] eczemas and neurodermitis

[0141] dermatitis such as, for example, seborrheic dermatitis orphotodermatitis

[0142] keratitis and keratoses such as, for example, seborrheickeratoses, senile keratoses, actinic keratosis, photo-induced keratosesor keratosis follicularis

[0143] keloids and keloid prophylaxis

[0144] warts, including condylomata or condylomata acuminata

[0145] human papilloma viral (HPV) infections such as, for example,venereal papillomata, viral warts such as, for example, molluscumcontagiosum, leukoplakia

[0146] popular dermatoses such as, for example, Lichen planus

[0147] skin cancer such as, for example, basal-cell carcinomas,melanomas or cutaneous T-cell lymphomas

[0148] localized benign epidermal tumors such as, for example,keratoderma, epidermal naevi

[0149] chilblains

[0150] high blood pressure

[0151] syndrome X

[0152] polycystic ovary syndrome (PCOS)

[0153] asthma

[0154] osteoarthritis

[0155] lupus erythematosus (LE) or inflammatory rheumatic disorders suchas, for example, rheumatoid arthritis

[0156] vasculitis

[0157] wasting (cachexia)

[0158] gout

[0159] ischemia/reperfusion syndrome

[0160] acute respiratory distress syndrome (ARDS)

[0161] Formulations

[0162] The amount of a compound of formula I necessary to achieve thedesired biological effect depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. The daily doseis generally in the range from 0.001 mg to 100 mg (typically from 0.01mg to 50 mg) per day and per kilogram of bodyweight, for example 0.1-10mg/kg/day. An intravenous dose may be, for example, in the range from0.001 mg to 1.0 mg/kg, which can suitably be administered as infusion of10 ng to 100 ng per kilogram and per minute. Suitable infusion solutionsfor these purposes may contain, for example, from 0.1 ng to 10 mg,typically from 1 ng to 10 mg, per milliliter. Single doses may contain,for example, from 1 mg to 10 g of the active ingredient. Thus, ampulesfor injections may contain, for example, from 1 mg to 100 mg, andsingle-dose formulations which can be administered orally, such as, forexample, capsules or tablets, may contain, for example, from 0.05 to1000 mg, typically from 0.5 to 600 mg. For the therapy of theabovementioned conditions, the compounds of formula I may be used as thecompound itself, but they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, beacceptable in the sense that it is compatible with the other ingredientsof the composition and is not harmful for the patient's health. Thecarrier may be a solid or a liquid or both and is preferably formulatedwith the compound as a single dose, for example as a tablet, which maycontain from 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of formula I. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

[0163] Pharmaceutical compositions of the invention are those suitablefor oral, rectal, topical, peroral (for example sublingual) andparenteral (for example subcutaneous, intramuscular, intradermal orintravenous) administration, although the most suitable mode ofadministration depends in each individual case on the nature andseverity of the condition to be treated and on the nature of thecompound of formula I used in each case. Coated formulations and coatedslow-release formulations also belong within the framework of theinvention. Preference is given to acid- and gastric juice-resistantformulations. Suitable coatings resistant to gastric juice comprisecellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

[0164] Suitable pharmaceutical preparations for oral administration maybe in the form of separate units such as, for example, capsules,cachets, suckable tablets or tablets, each of which contain a definedamount of the compound of formula I; as powders or granules, as solutionor suspension in an aqueous or nonaqueous liquid; or as an oil-in-wateror water-in-oil emulsion. These compositions may, as already mentioned,be prepared by any suitable pharmaceutical method which includes a stepin which the active ingredient and the carrier (which may consist of oneor more additional ingredients) are brought into contact. Thecompositions are generally produced by uniform and homogeneous mixing ofthe active ingredient with a liquid and/or finely divided solid carrier,after which the product is shaped if necessary. Thus, for example, atablet can be produced by compressing or molding a powder or granules ofthe compound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

[0165] Pharmaceutical compositions which are suitable for peroral(sublingual) administration comprise suckable tablets which contain acompound of formula I with a flavoring, normally sucrose and gum arabicor tragacanth, and pastilles which comprise the compound in an inertbase such as gelatin and glycerol or sucrose and gum arabic.

[0166] Pharmaceutical compositions suitable for parenteraladministration comprise preferably sterile aqueous preparations of acompound of formula I, which are preferably isotonic with the blood ofthe intended recipient. These preparations are preferably administeredintravenously, although administration may also take place bysubcutaneous, intramuscular or intradermal injection. These preparationscan preferably be produced by mixing the compound with water and makingthe resulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

[0167] Pharmaceutical compositions suitable for rectal administrationare preferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

[0168] Pharmaceutical compositions suitable for topical use on the skinare preferably in the form of ointment, cream, lotion, paste, spray,aerosol or oil. Carriers which can be used are petrolatum, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration of from 0.1 to 15% by weight of the composition, forexample from 0.5 to 2%.

[0169] Transdermal administration is also possible. Pharmaceuticalcompositions suitable for transdermal uses can be in the form of singleplasters which are suitable for long-term close contact with thepatient's epidermis. Such plasters suitably contain the activeingredient in an aqueous solution which is buffered where appropriate,dissolved and/or dispersed in an adhesive or dispersed in a polymer. Asuitable active ingredient concentration is about 1 % to 35%, preferablyabout 3% to 15%. A particular possibility is for the active ingredientto be released by electrotransport or iontophoresis as described, forexample, in Pharmaceutical Research, 2(6): 318 (1986).

[0170] The compounds of the formula I are distinguished by favorableeffects on metabolic disorders. They beneficially influence lipid andsugar metabolism, in particular they lower the triglyceride level andare suitable for the prevention and treatment of type II diabetes andarteriosclerosis and the diverse sequalae thereof.

[0171] Combinations with Other Medicaments

[0172] The compounds of the invention can be administered alone or incombination with one or more further pharmacologically active substanceswhich have, for example, favorable effects on metabolic disturbances ordisorders frequently associated therewith. Examples of such medicamentsare

[0173] 1. medicaments which lower blood glucose, antidiabetics,

[0174] 2. active ingredients for the treatment of dyslipidemias,

[0175] 3. antiatherosclerotic medicaments,

[0176] 4. antiobesity agents,

[0177] 5. antiinflammatory active ingredients

[0178] 6. active ingredients for the treatment of malignant tumors

[0179] 7. antithrombotic active ingredients

[0180] 8. active ingredients for the treatment of high blood pressure

[0181] 9. active ingredients for the treatment of heart failure andactive ingredients for the treatment and/or prevention of complicationscaused by diabetes or associated with diabetes.

[0182] They can be combined with the compounds of the invention of theformula I in particular for a synergistic improvement in the effect.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

[0183] Examples which may be mentioned are:

[0184] Antidiabetics

[0185] Suitable antidiabetics are disclosed for example in the RoteListe 2001, chapter 12 or in the USP Dictionary of USAN andInternational Drug Names, US Pharmacopeia, Rockville 2001. Antidiabeticsinclude all insulins and insulin derivatives such as, for example,Lantus® (see www.lantus.com) or Apidra®, and other fast-acting insulins(see U.S. Pat. No. 6,221,633), GLP-1 receptor modulators as described inWO 01/04146 or else, for example, those disclosed in WO 98/08871 of NovoNordisk A/S.

[0186] The orally effective hypoglycemic active ingredients include,preferably, sulfonylureas, biguanides, meglitinides,oxadiazolidinediones', thiazolidinediones, glucosidase inhibitors,glucagon antagonists, GLP-1 agonists, DPP-IV inhibitors, potassiumchannel openers such as, for example, those disclosed in WO 97/26265 andWO 99/03861, insulin sensitizers, inhibitors of liver enzymes involvedin the stimulation of gluconeogenesis and/or glycogenolysis, modulatorsof glucose uptake, compounds which alter lipid metabolism and lead to achange in the blood lipid composition, compounds which reduce foodintake, PPAR and PXR modulators and active ingredients which act on theATP-dependent potassium channel of the beta cells.

[0187] In one embodiment of the invention, the compounds of the formulaI are administered in combination with insulin.

[0188] In one embodiment of the invention, the compounds of the formulaI are administered in combination with substances which influencehepatic glucose production such as, for example, glycogen phosphorylaseinhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922,WO 03/104188)

[0189] In one embodiment, the compounds of the formula I areadministered in combination with a sulfonylurea such as, for example,tolbutamide, glibenclamide, glipizide or glimepiride.

[0190] In one embodiment, the compounds of the formula I areadministered in combination with an active ingredient which acts on theATP-dependent potassium channel of the beta cells, such as, for example,tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

[0191] In one embodiment, the compounds of the formula I areadministered in combination with a biguanide such as, for example,mefformin.

[0192] In a further embodiment, the compounds of the formula I areadministered in combination with a meglitinide such as, for example,repaglinide.

[0193] In one embodiment, the compounds of the formula I areadministered in combination with a thiazolidinedione such as, forexample, ciglitazone, pioglitazone, rosiglitazone or the compoundsdisclosed in WO 97/41097 of Dr. Reddy's Research Foundation, inparticular5-[[4-[(3,4-dihydro-3-methyl4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

[0194] In one embodiment, the compounds of the formula I areadministered in combination with a DPPIV inhibitor as described, forexample, in W098/19998, WO99/61431, WO99/67278, WO99/67279, WO01/72290,WO 02/38541, WO03/040174, in particular P 93/01(1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98,LAF237(1-[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile),TS021((2S,4S)4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]-acetyl]pyrrolidine-2-carbonitrilemonobenzenesulfonate).

[0195] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a PPARgamma agonist such as, forexample, rosiglitazone, pioglitazone.

[0196] In one embodiment, the compounds of the formula I areadministered in combination with compounds with an inhibitory effect onSGLT-1 and/or 2, as disclosed directly or indirectly for example inPCT/EP03/06841, PCT/EP03/13454 and PCT/EP03/13455.

[0197] In one embodiment, the compounds of the formula I areadministered in combination with an a-glucosidase inhibitor such as, forexample, miglitol or acarbose.

[0198] In one embodiment, the compounds of the formula I areadministered in combination with more than one of the aforementionedcompounds, e.g. in combination with a sulfonylurea and mefformin, asulfonylurea and acarbose, repaglinide and metformin, insulin and asulfonylurea, insulin and metformin, insulin and troglitazone, insulinand lovastatin, etc.

[0199] Lipid Modulators

[0200] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an HMGCOA reductase inhibitorsuch as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin,itavastatin, atorvastatin, rosuvastatin.

[0201] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a bile acid reabsorptioninhibitor (see, for example, U.S. Pat. No. 6,245,744, U.S. Pat. No.6,221,897, U.S. Pat. No. 6,277,831, EP 0683 773, EP 0683 774).

[0202] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a polymeric bile acid adsorbentsuch as, for example, cholestyramine, colesevelam.

[0203] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a cholesterol absorptioninhibitor as described for example in WO 0250027, or ezetimibe,tiqueside, pamaqueside.

[0204] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an LDL receptor inducer (see, forexample, U.S. Pat. No. 6,342,512).

[0205] In one embodiment, the compounds of the formula I areadministered in combination with bulking agents, preferably insolublebulking agents (see, for example, carob/Caromax® (Zunft H J; et al.,Carob pulp preparation for treatment of hypercholesterolemia, ADVANCESIN THERAPY (September-October 2001), 18(5), 230-6.) Caromax is acarob-containing product from Nutrinova, Nutrition Specialties & FoodIngredients GmbH, Industriepark Hoechst, 65926 Frankfurt/Main)).Combination with Caromax® is possible in one preparation or by separateadministration of compounds of the formula I and Caromax®. Caromaxe canin this connection also be administered in the form of food productssuch as, for example, in bakery products or muesli bars.

[0206] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a PPARalpha agonist.

[0207] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a mixed PPAR alpha/gamma agonistsuch as, for example, AZ 242 (Tesaglitazar,(S)-3-(4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionicacid), BMS 298585(N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine)or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169,WO96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO00/64876.

[0208] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a fibrate such as, for example,fenofibrate, gemfibrozil, clofibrate, bezafibrate.

[0209] In one embodiment of the invention, the compounds of the formulaI are administered in combination with nicotinic acid or niacin.

[0210] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a CETP inhibitor, e.g. CP-529,414 (torcetrapib).

[0211] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an ACAT inhibitor.

[0212] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an MTP inhibitor such as, forexample, implitapide.

[0213] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an antioxidant.

[0214] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipoprotein lipase inhibitor.

[0215] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an ATP citrate lyase inhibitor.

[0216] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a squalene synthetase inhibitor.

[0217] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipoprotein(a) antagonist.

[0218] Antiobesity Agents

[0219] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipase inhibitor such as, forexample, orlistat.

[0220] In one embodiment, the further active ingredient is fenfluramineor dexfenfluramine.

[0221] In another embodiment, the further active ingredient issibutramine.

[0222] In a further embodiment, the compounds of the formula I areadministered in combination with CART modulators (see“Cocaine-amphetamine-regulated transcript influences energy metabolism,anxiety and gastric emptying in mice” Asakawa, A, et al., M.: Hormoneand Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g.naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}amidehydrochloride (CGP 71 683A)), MC4 agonists (e.g.1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylicacid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide; (WO 01/91752)), orexinantagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A)), H3 agonists(3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists,P3 agonists (e.g.1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-ethanolhydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone)agonists, CCK-A agonists (e.g.{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptakeinhibitors (e.g. dexfenfluramine), mixed serotoninergic andnoradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g.1-(3-ethylbenzofuran-7-yl) piperazine oxalic acid salt (WO 01/09111),bombesin agonists, galanin antagonists, growth hormone (e.g. humangrowth hormone), growth hormone-releasing compounds(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tertiary butyl ester (WO 01/85695)), TRH agonists (see, forexample, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptinagonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin),lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO00/78312), RXR modulators or TR-β agonists.

[0223] In one embodiment of the invention, the further active ingredientis leptin.

[0224] In one embodiment, the further active ingredient isdexamphetamine, amphetamine, mazindole or phentermine.

[0225] In one embodiment, the compounds of the formula I areadministered in combination with medicaments having effects on thecoronary circulation and the vascular system, such as, for example, ACEinhibitors (e.g. ramipril), medicaments which act on theangiotensin-renine system, calcium antagonists, beta blockers etc.

[0226] In one embodiment, the compounds of the formula I areadministered in combination with medicaments having an antiinflammatoryeffect.

[0227] In one embodiment, the compounds of the formula I areadministered in combination with medicaments which are employed forcancer therapy and cancer prevention.

[0228] It will be appreciated that every suitable combination of thecompounds of the invention with one or more of the aforementionedcompounds and optionally one or more other pharmacologically activesubstances is regarded as falling within the protection conferred by thepresent invention.

[0229] The activity of the compounds was tested as follows:

[0230] Determination of EC50 Values of PPAR Agonists in the CellularPPARalpha Assay

[0231] Principle

[0232] The potency of substances which bind to human PPARalpha andactivate in an agonistic manner is analyzed using a stably transfectedHEK cell line (HEK=human embryo kidney) which is referred to here asPPARalpha reporter cell line. It contains two genetic elements, aluciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalphafusion protein (GR-GAL4-humanPPARalpha-LBD) which mediates expression ofthe luciferase reporter element depending on a PPARalpha ligand. Thestably and constitutively expressed fusion proteinGR-GAL4-humanPPARalpha-LBD binds in the cell nucleus of the PPARalphareporter cell line via the GAL4 protein portion to the GAL4 DNA bindingmotifs 5′-upstream of the luciferase reporter element which isintegrated in the genome of the cell line. There is only littleexpression of the luciferase reporter gene without addition of aPPARalpha ligand if fatty acid-depleted fetal calf serum (cs-FCS) isused in the assay. PPARalpha ligands bind and activate the PPARalphafusion protein and thereby bring about expression of the luciferasereporter gene. The luciferase which is formed can be detected by meansof chemiluminescence via an appropriate substrate.

[0233] Construction of the Cell Line

[0234] The PPARalpha reporter cell line was prepared in 2 stages.Firstly, the luciferase reporter element was constructed and stablytransfected into HEK cells. For this purpose, five binding sites of theyeast transcription factor GAL4 (each 5′-CGGAGTACTGTCCTCCGAG-3′) (SEQ IDNo.1) were cloned in 5′-upstream of a 68 bp-long minimal MMTV promoter(Genbank Accession #V01175). The minimal MMTV promoter section containsa CCMT box and a TATA element in order to enable efficient transcriptionby RNA polymerase 11. The cloning and sequencing of the GAL4-MMTVconstruct took place in analogy to the description of Sambrook J. et.al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Thenthe complete Photinus pyralis gene (Genbank Accession #M15077) wascloned in 3′-downstream of the GAL4-MMTV element. After sequencing, theluceriferase reporter element consisting of five GAL4 binding sites,MMTV promoter and luciferase gene was recloned into a plasmid whichconfers zeocin resistance in order to obtain the plasmidpdeltaM-GAL4-Luc-Zeo. This vector was transfected into HEK cells inaccordance with the statements in Ausubel, F.M. et al. (Currentprotocols in molecular biology, Vol. 1-3, John Wiley & Sons, Inc.,1995). Then zeocin-containing medium (0.5 mg/ml) was used to select asuitable stable cell clone which showed very low basal expression of theluceriferase gene. In a second step, the PPARalpha fusion protein(GR-GAL4-humanPPARalpha-LBD was introduced into the stable cell clonedescribed. For this purpose, initially the cDNA coding for theN-terminal 76 amino acids of the glucocorticoid receptor (GenbankAccession #P04150) was linked to the cDNA section coding for amino acids1-147 of the yeast transcription factor GAL4 (Genbank Accession#P04386). The cDNA of the ligand-binding domain of the human PPARalphareceptor (amino acids S167-Y468; Genbank Accession #S74349) was clonedin at the 3′-end of this GR-GAL4 construct. The fusion constructprepared in this way (GR-GAL4-humanPPARalpha-LBD) was recloned into theplasmid pcDNA3 (from Invitrogen) in order to enable constitutiveexpression therein by the cytomegalovirus promoter. This plasmid waslinearized with a restriction endonuclease and stably transfected intothe previously described cell clone containing the luciferase reporterelement. The finished PPARalpha reporter cell line which contains aluciferase reporter element and constitutively expresses the PPARalphafusion protein (GR-GAL4-human PPARalpha-LBD) was isolated by selectionwith zeocin (0.5 mg/ml) and G418 (0.5 mg/ml).

[0235] Assay Procedure

[0236] The activity of PPARalpha agonists is determined in a 3-day assaywhich is described below:

[0237] Day 1

[0238] The PPARalphareporter cell line is cultivated to 80% confluencein DMEM (#41965-039, Invitrogen) which is mixed with the followingadditions: 10% cs-FCS (fetal calf serum; #SH-30068.03, Hyclone), 0.5mg/ml zeocin (#R250-01, Invitrogen), 0.5 mg/ml G418 (#10131-027,Invitrogen), 1% penicillin-streptomycin solution (#15140-122,Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Thecultivation takes place in standard cell culture bottles (#353112,Becton Dickinson) in a cell culture incubator at 37° C. in the presenceof 5% CO₂. The 80%-confluent cells are washed once with 15 ml of PBS(#14190-094, Invitrogen), treated with 3 ml of trypsin solution(#25300-054, Invitrogen) at 37° C. for 2 min, taken up in 5 ml of theDMEM described and counted in a cell counter. After dilution to 500.000cells/ml, 35,000 cells are seeded in each well of a 96 well microtiterplate with a clear plastic base (#3610, Corning Costar). The plates areincubated in the cell culture incubator at 37° C. and 5% CO₂ for 24 h.

[0239] Day 2

[0240] PPARalpha agonists to be tested are dissolved in DMSO in aconcentration of 10 mM. This stock solution is diluted in DMEM(#41965-039, Invitrogen) which is mixed with 5% cs-FCS (#SH-30068.03,Hyclone), 2 mM L-glutamine (#25030-024, Invitrogen) and the previouslydescribed antibiotics (zeocin, G418, penicillin and streptomycin).

[0241] Test substances are tested in 11 different concentrations in therange from 10 μM to 100 pM. More potent compounds are tested inconcentration ranges from 1 μM to 10 pM or between 100 nM and 1 pM.

[0242] The medium of the PPARalpha reporter cell line seeded on day 1 iscompletely removed by aspiration, and the test substances diluted inmedium are immediately added to the cells. The dilution and addition ofthe substances is carried out by a robot (Beckman FX). The final volumeof the test substances diluted in medium is 100 μl per well of a 96 wellmicrotiter plate. The DMSO concentration in the assay is less than 0.1 %v/v in order to avoid cytotoxic effects of the solvent. Each plate wascharged with a standard PPARalpha agonist, which was likewise diluted in11 different concentrations, in order to demonstrate the functioning ofthe assay in each individual plate. The assay plates are incubated in anincubator at 37° C. and 5% CO₂ for 24 h.

[0243] Day 3

[0244] The PPARalpha reporter cells treated with the test substances areremoved from the incubator, and the medium is aspirated off. The cellsare lyzed by pipetting 50 μl of Bright Glo reagent (from Promega) intoeach well of a 96 well microtiter plate. After incubation at roomtemperature in the dark for 10 minutes, the microtiter plates aremeasured in the luminometer (Trilux from Wallac). The measuring time foreach well of a microtiter plate is 1 sec.

[0245] Evaluation

[0246] The raw data from the luminometer are transferred into aMicrosoft Excel file. Dose-effect plots and EC50 values of PPAR agonistsare calculated using the XL.Fit program as specified by the manufacturer(IDBS).

[0247] The PPARalpha EC50 values for the compounds of Examples 1 to 68in this assay are in the range from 3nM to >10 μM.

[0248] The results for the activity of some compounds of the inventionof the formula I are indicated in Table I below: TABLE I Example No.EC50 PPARalpha [nM] VIII 91 XX 1931 XXI 1251 XXIV 227 XXVI 709 XXVII 726XXXIV 114 XXXV 187

[0249] It is evident from Table I that the compounds of the invention ofthe formula I activate the PPARalpha receptor and thus bring about forexample in analogy to fibrates in clinical use a lowering oftriglycerides in the body (see, for example, J.-Ch. Fruchard et al.:PPARS, Metabolic Disease and Atherosclerosis, Pharmacological Research,Vol. 44, No. 5, 345-52, 2001; S. Kersten et al.: Roles of PPARs inhealth and disease, NATURE, VOL 405, 25 MAY 2000, 421-4; I. Pineda etal.: Peroxisome proliferator-activated receptors: from transcriptionalcontrol to clinical practice, Curr Opin Lipidol 12: 2001, 245-254).

[0250] Determination of EC50 Values of PPAR Agonists in the CellularPPARgamma Assay

[0251] Principle

[0252] A transient transfection system is employed to determine thecellular PPARgamma activity of PPAR agonists. It is based on the use ofa luciferase reporter plasmid (pGL3basic-5xGAL4-TK) and of a PPARgammaexpression plasmid (pcDNA3-GAL4-humanPPARgammaLBD). Both plasmids aretransiently transfected into human embryonic kidney cells (HEK cells).There is then expression in these cells of the fusion proteinGAL4-humanPPARgammaLBD which binds to the GAL4 binding sites of thereporter plasmid. In the presence of a PPARgamma-active ligand, theactivated fusion protein GAL4-humanPPARgammaLBD induces expression ofthe luciferase reporter gene, which can be detected in the form of achemiluminescence signal after addition of a luciferase substrate. As adifference from the stably transfected PPARalpha reporter cell line, inthe cellular PPARgamma assay the two components (luciferase reporterplasmid and PPARgamma expression plasmid) are transiently transfectedinto HEK cells because stable and permanent expression of the PPARgammafusion protein is cytotoxic.

[0253] Construction of the Plasmids

[0254] The luciferase reporter plasmid pGL3basic-5× GAL4-TK is based onthe vector pGL3basic from Promega. The reporter plasmid is prepared bycloning five binding sites of the yeast transcription factor GAL4 (eachbinding site with the sequence 5′-CTCGGAGGACAGTACTCCG-3′) (SEQ ID No.2), together with a 160 bp-long thymidine kinase promoter section(Genbank Accession #AF027128) 5′-upstream into pGL3basic. 3′-downstreamof the thymidine kinase promoter is the complete luciferase gene fromPhotinus pyralis (Genbank Accession #M15077) which is already aconstituent of the plasmid pGL3basic used. The cloning and sequencing ofthe reporter plasmid pGL3basic-5× GAL4-TK took place in analogy to thedescription in Sambrook J. et. al. (Molecular cloning, Cold SpringHarbor Laboratory Press, 1989).

[0255] The PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBDwas prepared by first cloning the cDNA coding for amino acids 1-147 ofthe yeast transcription factor GAL4 (Genbank Accession #P04386) into theplasmid pcDNA3 (from Invitrogen) 3′-downstream of the cytomegaloviruspromoter.

[0256] Subsequently, the CDNA of the ligand-binding domain (LBD) of thehuman PPARgamma receptor (amino acids 1152-Y475; Accession #g1480099)3′-downstream of the GAL4 DNA binding domain. Cloning and sequencing ofthe PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD againtook place in analogy to the description in Sambrook J. et. al.(Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Besidesthe luciferase reporter plasmid pGL3basic-5× GAL4-TK and the PPARgammaexpression plasmid pcDNA3-GAL4-humanPPARgammaLBD, also used for thecellular PPARgamma assay are the reference plasmid PRL-CMV (fromPromega) and the plasmid pBluescript SK(+) from Stratagene. All fourplasmids were prepared using a plasmid preparation kit from Qiagen,which ensured a plasmid quality with a minimal endotoxin content, beforetransfection into HEK cells.

[0257] Assay Procedure

[0258] The activity of PPARgamma agonists is determined in a 4-day assaywhich is described below. Before the transfection, HEK cells arecultivated in DMEM (#41965-039, Invitrogen) which is mixed with thefollowing additions: 10% FCS (#16000-044, Invitrogen), 1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen).

[0259] Day 1

[0260] Firstly, solution A, a transfection mixture which contains allfour plasmids previously described in addition to DMEM, is prepared. Thefollowing amounts are used to make up 3 ml of solution A for each 96well microtiter plate for an assay: 2622 μl of antibiotic- andserum-free DMEM (#41965-039, Invitrogen), 100 μl of reference plasmidPRL-CMV (1 ng/μl), 100 μl of luciferase reporter plasmid pGL3basic-5×GAL4-TK (10 ng/μl), 100 μl of PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD (100 ng/μl) and 78 μl of plasmidpBluescript SK(+) (500 ng/μl ). Then 2 ml of solution B are prepared bymixing 1.9 ml of DMEM (#41965-039, Invitrogen) with 100 μl of PolyFecttransfection reagent (from Qiagen) for each 96 well microtiter plate.Subsequently, 3 ml of solution A are mixed with 2 ml of solution B togive 5 ml of solution C, which is thoroughly mixed by multiple pipettingand incubated at room temperature for 10 min. 80%-confluent HEK cellsfrom a cell culture bottle with a capacity of 175 cm² are washed oncewith 15 ml of PBS (#14190-094, Invitrogen) and treated with 3 ml oftrypsin solution (#25300-054, Invitrogen) at 37° C. for 2 min. The cellsare then taken up in 15 ml of DMEM (#41965-039, Invitrogen) which ismixed with 10% FCS (#16000-044, Invitrogen), 1% penicillin-streptomycinsolution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024,Invitrogen). After the cell suspension has been counted in a cellcounter, the suspension is diluted to 250,000 cells/ml. 15 ml of thiscell suspension are mixed with 5 ml of solution C for one microtiterplate. 200 μl of the suspension are seeded in each well of a 96 wellmicrotiter plate with a clear plastic base (#3610, Corning Costar). Theplates are incubated in a cell culture incubator at 37° C. and 5% CO₂for 24 h.

[0261] Day 2

[0262] PPAR agonists to be tested are dissolved in DMSO in aconcentration of 10 mM. This stock solution is diluted in DMEM(#41965-039, Invitrogen) which is mixed with 2% Ultroser (#12039-012,Biosepra), 1 % penicillin-streptomycin solution (#15140-122, Invitrogen)and 2 mM L-glutamine (#25030-024, Invitrogen). Test substances aretested in a total of 11 different concentrations in the range from 10 pMto 100 pM. More potent compounds are tested in concentration ranges from1 pM to 10 pM.

[0263] The medium of the HEK cells transfected and seeded on day 1 iscompletely removed by aspiration, and the test substances diluted inmedium are immediately added to the cells. The dilution and addition ofthe substances is carried out by a robot (Beckman FX). The final volumeof the test substances diluted in medium is 100 μl per well of a 96 wellmicrotiter plate. Each plate is charged with a standard PPARgammaagonist, which is likewise diluted in 11 different concentrations, inorder to demonstrate the functioning of the assay in each individualplate. The assay plates are incubated in an incubator at 37° C. and 5%CO₂. Day 4

[0264] After removal of the medium by aspiration, 50 μl of Dual-Glo™reagent (Dual-Glo™ Luciferase Assay System; Promega) are added to eachwell in accordance with the manufacturer's instructions in order to lyzethe cells and provide the substrate for the firefly luciferase (Photinuspyralis) formed in the cells. After incubation at room temperature inthe dark for 10 minutes, the firefly luciferase-mediatedchemiluminescence is measured in a measuring instrument (measuringtime/well 1 sec; Trilux from Wallac). Then 50 μl of the Dual-Glo™ Stop &Glo reagent (Dual-Glo™ Luciferase Assay System; Promega) is added toeach well in order to stop the activity of the firefly luciferase andprovide the substrate for the Renilla luciferase expressed by thereference plasmid PRL-CMV. After incubation at room temperature in thedark for a further 10 minutes, a chemiluminescence mediated by theRenilla luciferase is again measured for 1 sec/well in the measuringinstrument.

[0265] Evaluation

[0266] The crude data from the luminometer are transferred into aMicrosoft Excel file. The firefly/Renilla luciferase activity ratio isdetermined for each measurement derived from one well of the microtiterplate. The dose-effect plots and EC50 values of PPAR agonists arecalculated from the ratios by the XL.Fit program as specified by themanufacturer (IDBS).

[0267] PPARgamma EC50 values in the range from 15nM to >10 μM weremeasured for the PPAR agonists described in this application.

[0268] The citation of any reference herein should not be construed asan admission that such reference is available as “Prior Art” to theinstant application.

[0269] The present invention is not to be limited in scope by thespecific embodiments describe herein. Indeed, various modifications ofthe invention in addition to those described herein will become apparentto those skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

[0270] Various publications are cited herein, the disclosures of whichare incorporated by reference in their entireties.

[0271] The examples given below serve to illustrate the invention, butwithout limiting it. TABLE II I

Ring A Ring B R1 R2 R3 X Y I 1,3-Cy

4-F H Me CH2-O --O—CH2-- II 1,3-Cy

4-F H Me CH2-O --O—CH2-- III 1,3-Cy

4-F H Me CH2-O --O—CH2-- IV 1,3-Cy

4-F H Me CH2-O --O—CH2-- V 1,3-Cy

4-F H Me CH2-O --O—CH2-- VI 1,3-Cy

4-F H Me CH2-O --O—CH2-- VII 1,3-Cy

4-F H Me CH2-O --O—CH2-- VIII 1,3-Cy

4-F H Me CH2-O --O—CH2-- IX 1,3-Cy

4-F H Me CH2-O --O—CH2-- X 1,3-Cy

4-F H Me CH2-O --O—CH2-- XI 1,3-Cy

4-F H Me CH2-O --O—C(═O)-- XII 1,3-Cy

4-F H Me CH2-O --O—C(═O)-- XIII 1,3-Cy

4-F H Me CH2-O --O—C(═O)-- XIV 1,3-Cy

4-F H Me CH2-O --O—C(═O)-- XV 1,3-Cy

4-F H Me CH2-O --O—C(═O)-- XVI 1,3-Cy

4-F H Me CH2-O --O—C(═O)-- XVII 1,3-Cy

4-F H Me CH2-O --O—C(═O)-- XVIII 1,3-Cy

4-F H Me CH2-O --O—C(═O)-- XIX 1,3-Cy

4-F H Me CH2-O --O—S(═O)2-- XX 1,3-Cy

4-F H Me CH2-O --O—S(═O)2-- XXI 1,3-Cy

4-F H Me CH2-O --O—S(═O)2-- XXII 1,3-Cy

4-F H Me CH2-O --O—CH2-CH═ XXIII 1,3-Cy

3-Me H Me CH2-O --O—CH2-CH═ XXIV 1,3-Cy

4-F H Me CH2-O --O—CH2-CH═ XXV 1,3-Cy

4-F H Me CH2-O --O—CH2-CH═ XXVI 1,3-Cy

4-F H Me CH2-O --O—CH2-CH-- XXVII 1,3-Cy

3-Me H Me CH2-O --O—CH2-CH-- XXVIII 1,3-Cy

3-Me H Me CH2-O --CH2-CH(OH)-- XXIX 1,3-Cy

3-OMe H Me CH2-O --CH2-CH(OH)-- XXX 1,3-Cy

4-Me H Me CH2-O --CH2-CH(OH)-- XXXI 1,3-Cy

3-Me H Me CH2-O --CH2-CH2-- XXXII 1,3-Cy

3-OMe H Me CH2-O --CH2-CH2-- XXXIII 1,3-Cy

4-Me H Me CH2-O --CH2-CH2-- XXXIV 1,3-Cy

4-Me H Me CH2-O --CH═ XXXV 1,3-Cy

4-Me H Me CH2-O --CH2-- XXXVI 1,3-Cy

3-OMe H Cy CH2-O --CH2-CH2-- XXXVII 1,3-Cy

4-Me H Cy CH2-O --CH2-CH2-- XXXVIII 1,3-Cy

3-CF₃ 5-CF₃ Et CH2-O --CH2-CH2-- XXXIX 1,3-Cy

2-Me 6-Me Et CH2-O --CH2-CH2-- XL 1,3-Cy

2-CF₃ H Me CH2-O --CH2-CH2-- XLI 1,3-Cy

3-OMe H Et CH2-O --CH2-CH2-- XLII 1,3-Cy

2-CF₃ H Et CH2-O --CH2-CH2-- XLIII 1,3-Cy

4-Me H Et CH2-O --CH2-CH2-- XLIV 1,3-Cy

4-^(i)Pr H Et CH2-O --CH2-CH2-- XLV 1,3-Cy

4-Me H ^(i)Pr CH2-O --CH2-CH2-- XLVI 1,3-Cy

3-CF₃ H Me CH2-O --CH2-CH2-- XLVIIa¹ 1,3-Cy

3-Me H Me CH2-O --CH2-CH2-- XLVIIb² 1,3-Cy

3-Me H Me CH2-O --CH2-CH2-- XLVIIIa² 1,3-Cy

4-^(i)Pr H Et CH2-O --CH2-CH2-- XLVIIIb¹ 1,3-Cy

4-^(i)Pr H Et CH2-O --CH2-CH2-- XLIXa² 1,3-Cy

4-Me H Me CH2-O --CH2-CH2-- XLIXb¹ 1,3-Cy

4-Me H Me CH2-O --CH2-CH2-- L² 1,3-Cy

3-Me 4-Me Et CH2-O --CH2-CH2-- LI² 1,3-Cy

4-CF₃ H Et CH2-O --CH2-CH2-- LII² 1,3-Cy

2-Naphthyl Et CH2-O --CH2-CH2-- LIII² 1,3-Cy

3-CF₃ H Et CH2-O --CH2-CH2-- LIV² 1,3-Cy

4-^(t)Bu H Et CH2-O --CH2-CH2-- LV² 1,3-Cy

3-Me 4-Me ^(i)Pr CH2-O --CH2-CH2-- LVI² 1,3-Cy

4-^(t)Bu H Et CH2-O --CH2-CH2-- LVII² 1,3-Cy

3-CF₃ H ^(i)Pr CH2-O --CH2-CH2-- LVIII² 1,3-Cy

4-^(t)Bu H ^(i)Pr CH2-O --CH2-CH2-- LIX² 1,3-Cy

4-^(t)Bu H ^(i)Pr CH2-O --CH2-CH2-- LX² 1,3-Cy

4-CF₃ H ^(i)Pr CH2-O --CH2-CH2-- LXI² 1,3-Cy

2-Naphthyl ^(i)Pr CH2-O --CH2-CH2-- LXII 1,3-Cy

3-OMe H Me CH2-O --CH2-CH2-- LXIII 1,3-Cy

3-OMe H Me CH2-O --CH2-CH2-- LXIV 1,3-Cy

4-Me H Me CH2-O --CH2-CH2-- LXV 1,3-Cy

4-Me H Me CH2-O --CH2-CH2-- LXVI 1,3-Cy

3-OMe H ^(i)Pr CH2-O --CH2-CH2-- LXVII 1,3-Cy

3-OMe H Ph CH2-O --CH2-CH2-- LXVIII 1,3-Cy

3-OMe H Ph CH2-O --CH2-CH2--

[0272] Also described is a process for preparing the compounds of theformula I according to reaction schemes A to H below:

[0273] Initially, cyclohexanediol is heated with dibutyltin oxide intoluene on a water separator for a number of hours and then, withaddition of dimethylformamide, cesium fluoride and an oxazole of theformula A1 in which R1, R2 and R3 are as defined above, converted bystirring at room temperature for a number of hours into a compound ofthe formula A2 in which R1, R2 and R3 are as defined above.

[0274] The compound of the formula A2 is reacted using Chirazyme L2 andvinyl acetate. This results in the formation of compounds A3 and A4, ofwhich A4, after separation, is reacted with alkali metal hydroxides togive a compound of the structure A5 in which R1, R2 and R3 are asdefined above.

[0275] The compound of the formula A5 or A2 is converted into anenantiomerically pure or racemic compound of the structure A6 in whichR1, R2 and R3 are as defined above. To form the ether bond, A5 or A2 isdeprotonated, for example in an aprotic solvent such asdimethylformamide, using strong bases, for example sodium hydride, andreacted with unsaturated bromides, for example allyl bromides.

[0276] The enantiomerically pure or racemic compound of the formula A6is, using osmium tetroxide and sodium periodate, converted into theenantiomerically pure or racemic compound of the structure A7 in whichR1, R2 and R3 are as defined above.

[0277] The enantiomerically pure or racemic compound of the formula A7is converted into enantiomerically pure or racemic compounds of thestructure A8 in which R1, R2 and R3 are as defined above. Here,thiazolidinedione is initially deprotonated in an inert solvent using astrong base, for example n-butyllithium, and then, at −70° C., reactedwith component A7, giving, after acidic work-up, for example with 6Nhydrochloric acid, the compound A8.

[0278] The enantiomerically pure or racemic compound A8 is, byhydrogenation, using, for example, palladium-on-carbon as catalyst insolvents such as methanol or ethyl acetate, converted into anenantiomerically pure or racemic compound of the formula A9 in which R1,R2 and R3 are as defined above.

[0279] The compound of the formula B4 in which R1, R2 and R3 are asdefined above is obtained from lactone B1 by lithium aluminum hydridereduction to diol B2, selective silylation at the primary alcoholfunction giving compound B3, deprotonation using strong bases, forexample sodium hydride in an aprotic solvent such as dimethylformamide,and alkylation with phenyloxazoyl iodides of the formula A1, in whichR1, R2 and R3 are as defined above.

[0280] The compound of the formula B4 in which R1, R2 and R3 are asdefined above is converted into a compound of the structure B5 in whichR1, R2 and R3 are as defined above, for example by removing the silylprotective group with fluoride, for example tetrabutylammonium fluoride.

[0281] Using osmium tetroxide and sodium periodate, the compound of theformula B5 is converted into the compound of the structure B6 in whichR1, R2 and R3 are as defined above.

[0282] The compound of the formula B6 is converted into a compound ofthe structure B7 in which R1, R2 and R3 are as defined above. Here,thiazolidinedione is initially deprotonated in an inert solvent using astrong base, such as, for example, n-butyllithium, and then, at −70° C.,reacted with component B6 giving, after acidic work-up, for example with6N hydrochloric acid, compound B7.

[0283] Compound B7 is converted by hydrogenation, for example at ahydrogen pressure of 3 bar using palladium-on-carbon as catalyst insolvents such as methanol or ethyl acetate, into a compound of theformula B8 in which R1, R2 and R3 are as defined above.

[0284] Compounds of the formula A1 in which R1, R2 and R3 are as definedabove are dissolved with cis-3-allylcyclohexanol C1 (or optionally with(1 S,3S)-3-allylcyclohexanol C7) in aprotic solvents, such asdimethylformamide, and reacted with strong bases, such as, for example,sodium hydride, giving compounds of the formula C2 in which R1, R2 andR3 are as defined above.

[0285] The compound of the formula C2 is, using osmium tetroxide andsodium periodate, converted into the compound of the structure C3 inwhich R1, R2 and R3 are as defined above.

[0286] The compound of the formula C3 is converted into a compound ofthe structure C4 in which R1, R2, R3 and R4 are as defined above. Here,thiazolidinedione is initially deprotonated in an inert solvent using astrong base, such as, for example, n-butyllithium, and then, at −70° C.,reacted with component C3, giving, after work-up, for example with 1Nhydrochloric acid, a compound of the formula C4.

[0287] The compound C4 is converted into a compound of the formula C5 inwhich R1, R2, R3 and R4 are as defined above. Alcohol C4 is, forexample, mixed with mesyl chloride and triethylamine in polar solvents,such as dichloromethane, and the crude product is, at −70° C., convertedwith n-butyllithium into C5.

[0288] The compound of the formula C5 is converted by hydrogenation, forexample at a hydrogen pressure of 5 bar using palladium-on-carbon ascatalyst in ethyl acetate, into a compound of the formula C6 in whichR1, R2, R3 and R4 are as defined above.

[0289] Enantiomerically pure (1S,3S)-3-allylcyclohexanol C7 can beobtained from racemic C1 by treatment with lipase in vinyl acetate. Thecoproduct (1R,3R)-3-allylcyclohexanyl acetate C8 can be removedchromatographically.

[0290] The compound of the formula A5 or A2 is converted using bases,for example cesium hydroxide in a mixture of water and acetonitrile,using a phase-transfer catalyst, for example tetrabutylammonium iodide,with nitrobenzyl bromides of the formula D1 into enantiomerically pureor racemic compounds of the structure D2 in which R1, R2 and R3 are asdefined above.

[0291] The compound of the formula A5 or A2 is, using strong bases, forexample sodium hydride, deprotonated in an aprotic solvent and reactedwith cyanobenzyl bromides of the formula E1, giving enantiomericallypure or racemic compounds of the structure E2 in which R1, R2 and R3 areas defined above. The compound of the formula E2 is, using a metalazide, for example tributyltin azide, converted into enantiomericallypure or racemic compounds of the structure E3 in which R1, R2, and R3are as defined above.

[0292] The compound of the formula A5 or A2 is, using bases, for examplepyridine, reacted at about 50° C. with nitrobenzoyl chlorides of theformula F1, giving enantiomerically pure or racemic compounds of theformula F2 in which R1, R2 and R3 are as defined above.

[0293] The compound of the formula A5 or A2 is, using bases, for examplepyridine, reacted at about 50° C. with cyanobenzoyl chlorides of theformula G1, giving enantiomerically pure or racemic compounds of theformula G2 in which R1, R2 and R3 are as defined above.

[0294] The compound of the formula G2 is, using a metal azide, forexample tributyltin azide, converted at about 160° C. intoenantiomerically pure or racemic compounds of the structure G3 in whichR1, R2 and R3 are as defined above.

[0295] The compound of the formula A5 or A2 is, using bases, for examplepyridine, reacted at room temperature with nitrobenzenesulfonylchlorides of the formula G1, giving enantiomerically pure or racemiccompounds of the formula G2 in which R1, R2 and R3 are as defined above.

[0296] The abbreviations used denote:

[0297] Ac acetyl

[0298]^(i)Bu isobutyl

[0299]^(t)Bu tert-butyl

[0300] BuLi n-butyllithium

[0301] Cy cyclohexyl

[0302] TLC thin-layer chromatography

[0303] DCI direct chemical ionization (MS)

[0304] DCM dichloromethane

[0305] DMAP 4-N,N-dimethylaminopyridine

[0306] DMF N,N-dimethylformamide

[0307] DMSO dimethyl sulfoxide

[0308] EA ethyl acetate

[0309] EDC N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl

[0310] El electron impact ionization (MS)

[0311] eq equivalent

[0312] ESI electron spray ionization (MS)

[0313] Et ethyl

[0314] Sat. saturated

[0315] h hour

[0316] HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium

[0317] hexafluorophosphate

[0318] HOBt 1-hydroxy-1H-benzotriazole×H₂O

[0319] HPLC high pressure, high performance liquid chromatography

[0320] LC-MS liquid-chromatography-coupled mass spectroscopy

[0321] Me methyl

[0322] MS mass spectroscopy

[0323] MsCl methanesulfonyl chloride

[0324] NMR nuclear magnetic resonance spectroscopy

[0325] Pd/C palladium-on-carbon

[0326]^(i)Pr isopropyl

[0327]^(n)Pr n-propyl

[0328] R_(f) retention time (TLC)

[0329] RT room temperature

[0330] TBAF tetrabutylammonium fluoride

[0331] TBAl tetrabutylammonium iodide

[0332] TBDPSCl tert-butyld iphenyIsilyl chloride

[0333] THF tetrahydrofuran

[0334] Other compounds of the formula I to be obtained by knownprocesses are in accordance with the reaction schemes described above.

EXAMPLE I2-(4-Fluorophenyl)-5-methyl-4-[cis-3-(2-cyanobenzyloxy)cyclohexyl-oxymethyl]oxazole

[0335]

rac-3-(cis-5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexanol

[0336]

[0337] 21.7 g of 1,3-cyclohexanediol and 30.3 g of dibutyltin oxide aredissolved in 450 ml of toluene and, under reflux on a water separator,heated to boiling. During the reaction, the reaction volume is reducedto half the original volume. After 3 hours, the reaction mixture iscooled to room temperature, and 300 ml of dimethylformamide, 29 g of2-(4-fluorophenyl)-4-iodomethyl-5-methyloxazole 1 and 23.5 g of cesiumfluoride are added. The mixture is stirred at room temperature for 18hours. The reaction mixture is diluted by addition of ethyl acetate andwashed with saturated sodium chloride solution. The organic phase isdried over magnesium sulfate, the solvent is removed under reducedpressure and the residue is purified by flash chromatography on silicagel (n-heptane/ethyl acetate=10:1→1:4). This gives 58 g ofrac-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol as ayellowish solid which is recrystallized from n-heptane/ethyl acetate.C₁₇H₂₀FNO₃ (305.35), MS (ESI): 306 (M+H⁺).

(1R,3S)-3-[2-(4-Fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexanol

[0338]

[0339] 25 g ofrac-cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanolare dissolved in 320 ml of vinyl acetate, and 1.3 g of Chirazyme L-2 Lyo(Boehringer Mannheim) are added. The mixture is stirred at roomtemperature for three hours (checked by LC-MS for 40-45% conversion) andthe enzyme is then filtered off and washed with ethyl acetate, and thesolvent is removed under reduced pressure. The residue is purified byflash chromatography on silica gel (n-heptane/ethyl acetate=3:1). Thisgives 8 g of (1 R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazyol-4-ylmethoxy]cyclohexyl acetateas a colorless oil. C₁₉H₂₂FNO4 (347.39), MS (ESI): 348 (M+H⁺). Theacetate is taken up in 170 ml of methanol and, after addition of 27 mlof 2N aqueous sodium hydroxide solution, stirred at room temperature forone hour. Most of the solvent is removed under reduced pressure. Afteraddition of in each case 150 ml of water and ethyl acetate, the organicphase is washed with sodium chloride solution. The organic phase isdried over magnesium sulfate and the solvent is removed under reducedpressure. This gives 6.7 g of3-(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexanolas a yellowish solid. C₁₇H₂₀FNO₃ (305.35), MS (ESI): 306 (M+H⁺).

2-(4-Fluorophenyl)-5-methyl4-[cis-3-(2-cyanobenzyloxy)cyclohexyl-oxymethyl]oxazole

[0340]

[0341] In a 25 ml two-necked flask which had been dried by heating, 0.15g of the alcohol3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol isdissolved in 5 ml of dimethylformamide (dry), and 0.05 g of sodiumhydride is added. The mixture is stirred for 15 minutes, 0.19 g of2-(bromomethyl)benzonitrile is then added, and the mixture is stirred atroom temperature for 24 hours. The reaction is terminated by addition of2 ml of 1N hydrochloric acid and the mixture is extracted with ethylacetate (2×10 ml). The combined organic phases are washed with saturatedsodium chloride solution and dried over magnesium sulfate and thesolvent is then removed under reduced pressure. Purification bypreparative HPLC gives 0.07 g of the desired product2-(4-fluorophenyl)-5-methyl-4-[cis-3-(2-cyanobenzyloxy)cyclohexyloxymethyl]oxazoleas a colorless oil. C₂₅H₂₅FN₂O₃ (420.48), MS (ESI): 421 (M+H⁺).

EXAMPLE II2-(4-Fluorophenyl)-5-methyl4-[cis-3-(3-cyanobenzyloxy)cyclohexyloxy-methyl]oxazole

[0342] Analogously to Example I, the alcohol3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexanol and3-(bromomethyl)benzonitrile give the compound2-(4-fluorophyenyl)-5-methyl-4-[cis-3-(3-cyanobenzyloxy)-cyclohexyloxymethyl]oxazole:

[0343] C₂₅H₂₅FN₂0₃ (420.48), MS (ESI): 421 (M+H⁺).

EXAMPLE III2-(4-Fluorophenyl)-5-methyl-4-[cis-3-(4-cyanobenzyloxy)cyclohexyl-oxymethyl]oxazole

[0344] Analogously to Example I, the alcohol3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and4-(bromomethyl)benzonitrile give the compound2-(4-fluorophenyl)-5-methyl-4-[cis-3-(4-cyanobenzyloxy)-cyclohexyloxymethyl]oxazole:

[0345] C₂₅H₂₅FN₂O₃ (420.48), MS (ESI): 421 (M+H⁺).

[0346] The compounds synthesized in this manner (Example I-III) can beconverted into the corresponding tetrazoles:

EXAMPLE IV5-(2-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclo-hexyloxymethyl}phenyl)-1-H-tetrazole

[0347]

[0348] 0.03 g of the nitrile2-(4-fluorophenyl)-5-methyl-4-[cis-3-(2-cyanobenzyloxy)cyclohexyloxymethyl]oxazole are dissolved in 5 ml of xylene, 50 μl of tributyltin azide areadded and the mixture is heated under reflux at 160° C. for 24 hours.The reaction is terminated by addition of 1 ml of trifluoroacetic acid(in 1 ml of methanol), 3 ml of water are added and the mixture isextracted with ethyl acetate (2×10 ml). The combined organic phases arewashed with saturated sodium chloride solution and dried over magnesiumsulfate, and the solvent is then removed under reduced pressure.Purification by preparative HPLC gives 0.02 g of the desired5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy-methyl}phenyl)-1-H-tetrazoleas an amorphous solid. C₂₅H₂₆FN₅O₃ (463.51), MS (ESI): 464 (M+H⁺).

EXAMPLE V5-(3-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexyloxymethyl}phenyl)-1H-tetrazole

[0349] Analogously to Example IV,2-(4-fluorophenyl)-5-methyl4-[cis-3-(3-cyanobenzyloxy)cyclohexyloxymethyl]oxazole from Example II gave, by reaction with tributyltin hydride,5-(3-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexyloxymethyl}phenyl)-1H-tetrazole:

[0350] C₂₅H₂₆FN₅O₃ (463.51), MS (ESI): 464 (M+H⁺).

EXAMPLE VI5-(4-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclo-hexyloxymethyl}phenyl)-1H-tetrazole

[0351] Analogously to Example IV,2-(4-fluorophenyl)-5-methyl4-[cis-3-(4-cyanobenzyloxy)cyclohexloxymethyl]oxazolefrom Example III gave, by reaction with tributyltin hydride,5-(4-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexyloxymethyl}phenyl)-1H-tetrazole:

[0352] C₂₅H₂₆FN₅O₃ (463.51), MS (ESI): 464 (M+H⁺).

EXAMPLE VII2-(4-Fluorophenyl)-5-methyl4-[cis-3-(2-nitrobenzyloxy)cyclohexyloxy-methyl]oxazole

[0353]

[0354] 0.1 g of3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol isdissolved in 3 ml of acetonitrile, and 0.21 g of 2-nitrobenzyl bromideand 0.36 g of tetrabutylammonium iodide are added. 0.57 ml of cesiumhydroxide solution (50% strength solution in water) is added dropwise,and the two-phase mixture is stirred vigorously at room temperature, for12 hours. The reaction is checked (LCMS), showing the formation of thedesired product, in addition to unreacted alcohol3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexanol. Byaddition of a further 0.2 g of 2-nitrobenzyl bromide (2 eq) at roomtemperature and stirring at room temperature for a further 12 hours, thereaction is terminated by addition of 2 ml of 1N hydrochloric acid andthe mixture is extracted with ethyl acetate (2×10 ml). The combinedorganic phases are washed with saturated sodium chloride solution anddried over magnesium sulfate. Purification by HPLC gives 0.05 g of thecompound2-(4-fluorophenyl)-5-methyl4-[cis-3-(2-nitrobenzyloxy)cyclohexyloxymethyl]oxazoleas a clear colorless oil.

[0355] C₂₄H₂₅FN₂O₅ (440.47), MS (ESI): 441 (M+H⁺).

EXAMPLE VIII2-(4-Fluorophenyl)-5-methyl4-[cis-3-(3-nitrobenzyloxy)cyclohexyloxy-methyl]oxazole

[0356] Analogously to Example VII,3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and3-nitrobenzyl bromide gave the compound2-(4-fluorophenyl)-5-methyl4-[cis-3-(3-nitrobenzyloxy)cyclohexyloxy-methyl]oxazolebelow:

[0357] C₂₄H₂₅FN₂O₅ (440.47), MS (ESI): 441

EXAMPLE IX2-(4-Fluorophenyl)-5-methyl4-[cis-3-(4-nitrobenzyloxy)cyclohexyloxy-methyl]oxazole

[0358] Analogously to Example VII,3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and4-nitrobenzyl bromide gave the compound2-(4-fluorophenyl)-5-methyl4-[cis-3-(4-nitrobenzyloxy)cyclohexyloxy-methyl]oxazolebelow:

[0359] C₂₄H₂₅FN₂O₅ (440.47), MS (ESI): 441

EXAMPLE X 2-(4-Fluorophenyl)4-[cis-3-(2-methoxy-5-nitrobenzyloxy)cyclohexyloxy-methyl]-5-methyloxazole

[0360] Analogously to Example VII,cis-3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexanol and2-methoxy-5-nitrobenzyl bromide gave the compound2-(4-fluorophenyl)-4-[cis-3-(2-methoxy-5-nitrobenzyloxy)cyclo-hexyloxymethyl]-5-methyloxazolebelow:

[0361] C₂₅H₂₇FN₂O₆ (470.50), MS (ESI): 471 (M+H⁺)

EXAMPLE XI cis-3-[2-(4-Fluorophenyl )-5-methyloxazol-4-ylmethoxy]cyclohexyl 3,5-dinitrobenzoate

[0362]

[0363] 0.5 g of3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol isdissolved in 3 ml of pyridine and, at 0° C., 0.6 g of 3,5-dinitrobenzoylchloride is added. The reaction mixture is then heated at 50° C. for 10minutes. The reaction is checked (LCMS) showing the formation of thedesired product, in addition to unreacted alcoholcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol. Aftera further 10 minutes of stirring at room temperature, the reaction isterminated by addition of 5 ml of concentrated hydrochloric acid, andthe crude product is filtered off with suction, taken up in ethylacetate, washed with saturated sodium bicarbonate and sodium chloridesolution and dried over magnesium sulfate. Purification by HPLC gives0.15 g of the compound cis-3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexyl 3,5-dinitrobenzoate as yellowsolid.

[0364] C₂₄H₂₂FN₃O₈ (499.46), MS (ESI): 500 (M+H⁺).

EXAMPLE XIIcis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl3-methyl-5-nitrobenzoate

[0365] Analogously to Example XI,cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and3-methyl-5-nitrobenzoyl chloride gave the compoundcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl3-methyl-5-nitrobenzoate below:

[0366] C₂₅H₂₅FN₂O₆ (468.48), MS (ESI): 469 (M+H⁺).

EXAMPLE XIIIcis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl3-nitrobenzoate

[0367] Analogously to Example XI,cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and3-nitrobenzoyl chloride gave the compoundcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl3-nitrobenzoate below:

[0368] C₂₄H₂₃FN₂O₆ (454.46), MS (ESI): 455 (M+H⁺).

EXAMPLE XIVcis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl2-nitrobenzoate

[0369] Analogously to Example XI,cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and2-nitrobenzoyl chloride gave the compoundcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl2-nitrobenzoate below:

[0370] C₂₄H₂₃FN₂O₆ (454.46), MS (ESI): 455 (M+H⁺).

EXAMPLE XVcis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl3-cyanobenzoate

[0371] Analogously to Example XI,cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and3-cyanobenzoyl chloride gave the compoundcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl3-cyanobenzoate below:

[0372] 0.1 g of3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol isdissolved in 3 ml of pyridine and, at 0° C., 0.1 g of 3-cyanobenzoylchloride is added. The reaction mixture is then heated at 50° C. for 10minutes. The reaction is checked (LCMS), showing the formation of thedesired product in addition to unreacted alcoholcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol. Afteraddition of a further 0.9 g of 3-cyanobenzoyl chloride and 30 minutes ofstirring at room temperature, the reaction is terminated by addition of5 ml of concentrated hydrochloric acid, the mixture is extracted withethyl acetate and the organic phase is washed with saturated sodiumbicarbonate and sodium chloride solution and dried over magnesiumsulfate. Purification by HPLC gives 0.1 g of the compoundcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl3-cyanobenzoate as a brown solid.

[0373] C₂₅H₂₃FN₂O₄ (434.47), MS (ESI): 435 (M+H⁺).

EXAMPLE XVIcis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl4-cyanobenzoate

[0374] Analogously to Example XI,cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and4-cyanobenzoyl chloride gave the compoundcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl4-cyanobenzoate below:

[0375] C₂₅H₂₃FN₂O₄ (434.47), MS (ESI): 435 (M+H⁺).

[0376] The compounds synthesized in this manner (Examples XV-XVI) can beconverted into the corresponding tetrazoles by reaction with tributyltinazide.

EXAMPLE XVIIcis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl3-(1H-tetrazol-5-yl)benzoate

[0377]

[0378] 0.06 g ofcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl3-cyanobenzoate is dissolved in 5 ml of xylene, 150 μm of tributyltinazide are added and the mixture is heated under reflux at 160° C. for 24hours. The reaction is terminated by addition of 1 ml of trifluoroaceticacid (in 1 ml of methanol), 3 ml of water are added and the mixture isextracted with ethyl acetate (2×10 ml). The combined organic phases arewashed with saturated sodium chloride solution and dried over magnesiumsulfate, and the solvent is then removed under reduced pressure.Purification by preparative HPLC gives 0.04 g of the desiredcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl3-(1H-tetrazol-5-yl)benzoate as an amorphous solid.

[0379] C₂₅H₂₄FN₅O₄ (477.49), MS (ESI): 478 (M+H⁺).

EXAMPLE XVIIIcis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl4-cyanobenzoate

[0380] Analogously to Example XVII,cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl4-cyanobenzoate and tributyltin hydride gavecis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl4-cyanobenzoate:

[0381] C₂₅H₂₄FN₅O₄ (477.49), MS (ESI): 478 (M+H⁺).

EXAMPLE XIXcis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl4-methyl-3-nitrobenzenesulfonate

[0382]

[0383] 0.1 g ofcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl and 0.15of 4-methyl-3-nitrobenzenesulfonyl chloride are dissolved in 10 ml ofdry chloroform and, at 0° C., 2 ml of pyridine are added. The reactionmixture is then stirred at room temperature for 12 hours. The reactionis checked (LCMS), showing the formation of the desired product, inaddition to unreacted alcoholcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol. Aftera further 10 minutes of stirring at room temperature, the reaction isterminated by addition of 2 ml of concentrated hydrochloric acid, themixture is extracted with dichloromethane and the extract is washed withsaturated sodium bicarbonate and sodium chloride solution and dried overmagnesium sulfate. Purification by HPLC gives 0.14 g of the compoundcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl4-methyl-3-nitrobenzenesulfonate as a viscous oil

[0384] C₂₄H₂₅FN₂O₇S (504.53), MS (ESI): 505 (M+H⁺).

EXAMPLE XX cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 2-chloro-5-nitrobenzoate

[0385] Analogously to Example XIX,cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl and2-chloro-5-nitrobenzenesulfonic acid gave the compoundcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl2-chloro-5-nitrobenzenesulfonate:

[0386] C₂₃H₂₂FClN₂O₇S (524.95), MS (ESI): 525 (M+H⁺).

EXAMPLE XXIcis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl4-methoxy-2-nitrobenzesulfonate

[0387] Analogously to Example XIX,cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and4-methoxy-2-nitrobenzenesulfonic acid gavecis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl4-methoxy-2-nitrobenzenesulfonate;

[0388] C₂₄H₂₅FN₂O₈S (520.53), MS (ESI): 521 (M+H⁺)

EXAMPLE XXII5-(2-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}-ethylidene)thiazolidine-2,4-dione4-(cis-3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole

[0389]

[0390] 2 g ofcis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol aredissolved in 15 ml of dimethylformamide, and 0.3 g of sodium hydride isadded. After 30 minutes, 2.4 g of allyl bromide are added dropwise. Themixture is stirred at room temperature for 5 hours. 15 ml of 1Nhydrochloric acid are then added to the reaction mixture, and themixture is washed three times with 15 ml of ethyl acetate. The organicphase is dried over magnesium sulfate and the solvent is then removedunder reduced pressure. The residue is purified by RP-HPLC. This gives2.4 g of4-(cis-3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazoleas a yellowish oil. C₂₀H₂₄FNO₃ (345.42), MS (ESI): 346 (M+H⁺)

[cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde

[0391]

[0392] 2.0 g of4-(cis-3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyl-oxazoleare dissolved in 50 ml of diethyl ether, and 3.8 g of sodium periodate,dissolved in 50 ml of water, are added. At 0° C., 1 ml of an osmiumtetroxide solution (2.5% by weight in tert-butanol) is added, and themixture is stirred vigorously at room temperature. After 8 hours, 100 mlof methyl tert-butyl ether are added, and the mixture is washed with asaturated sodium thiosulfate solution. The organic phase is dried overmagnesium sulfate and the solvent is removed under reduced pressure. Theresidue is purified on silica gel (n-heptane:ethyl acetate=1:1→1:5).This gives 1.4 g of[cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehydeas a colorless oil. C₂₀H₂₅NO₄ (343.42), MS (ESI): 344 (M+H⁺),R_(f)(n-heptane:ethylacetate=1:1)=0.25.

5-(2-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy)-ethylidene)thiazolidine-2,4-dione

[0393]

[0394] 66 mg of thiazolidinedione are dissolved in 10 ml oftetrahydrofuran and, at −78° C., 0.11 ml of a 2.7 M solution ofn-butyllithium in n-hexane is added. The mixture is stirred at −78° C.for 30 minutes, and 150 mg of[cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde,dissolved in 5 ml of tetrahydrofuran, are then added. After 30 minutesof stirring at −78° C., the mixture is allowed to warm to roomtemperature. 5 ml of 1N hydrochloric acid are added, and the mixture isextracted three times with in each case 20 ml of ethyl acetate. Thecombined organic phases are dried over magnesium sulfate and the solventis then removed under reduced pressure. The residue is purified byRP-HPLC. This gives 184 mg of5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-oxy}ethylidene)thiazolidine-2,4-dioneas a white solid.

[0395] C₂₂H₂₃FN₂O₅S (446.01), MS (ESI): 447 (M+H⁺).

EXAMPLE XXIII5-[2-[3-(5-Methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethylidene]-thiazolidine-2,4-dione

[0396] Analogously to Example XXII,[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde andthiazolidinedione gave the compound5-[2-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyloxy}-ethylidene]thiazolidine-2,4-dione:

[0397] C₂₃H₂₆N₂O₅S (442.53), MS (ESI): 443 (M+H⁺).

EXAMPLE XXIV5-[2-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}-ethylidene]imidazolidine-2,4-dione

[0398] Analogously to Example XXII,[3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehydeand hydantoin gave the compound5-[2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}-ethylidene]imidazolidine-2,4-dione:

[0399] C₂₂H₂₄FN₃O₅ (429.45), MS (ESI): 430 (M+H⁺)

EXAMPLE XXV5-[2-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}-ethylidene]-2-thioxoimidazolidine-2,4-dione

[0400] Analogously to Example XXII,[cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehydeand 2-thioxoimidazolidin-4-one gave5-[2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy)cyclohexyloxy)-ethylidene)-2-thioxoimidazolidine-4-one:

[0401] C₂₂H₂₄FN₃O₄S (445.51), MS (ESI): 446 (M+H⁺)

EXAMPLE XXVI5-(2-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}-ethyl)thiazolidine-2,4-dione

[0402] Hydrogenation of the compound5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}ethylidene)thiazolidine-2,4-dione,mentioned in Example Example XXII, with hydrogen gives the compound5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-oxy}ethyl)thiazolidine-2,4-dione:

[0403] 180 mg of the unsaturated5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}ethylidene)thiazolidine-2,4-dioneis dissolved in 10 ml of ethyl acetate, and 20 mg ofpalladuium-on-carbon are added. The mixture is then stirred at roomtemperature under a hydrogen pressure of 2 bar for 2 hours. The catalystis filtered off, the solvent is removed under reduced pressure and theresidue is purified by RP-HPLC. This gives 140 mg of the compound5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}ethyl)thiazolidine-2,4-dioneas a yellowish solid.

[0404] C₂₂H₂₅FN₂O₅S (448.01), MS (ESI): 449 (M+H⁺)

EXAMPLE XXVII5-{2-[(cis-3-(5-Methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}thiazolidine-2,4-dione

[0405] As in Example XXVI, hydrogenation of the compound5-[2-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethylidene]thiazolidine-2,4-dione,mentioned in Example Example XXIII, with hydrogen gives the compound5-{2-[(cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}thiazolidine-2,4-dione:

[0406] C₂₃H₂₈N₂O₅S (444.55), MS (ESI): 445 (M+H⁺)

EXAMPLE XXVIII5-{2-[cis-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazol-idine-2,4-dione4-(cis-3-Allylcyclohexyloxymethyl)-2-(3-methylphenyl)-5-methyloxazole

[0407]

[0408] 2 g of cis-3-allylcyclohexanol are dissolved in 30 ml ofdimethylformamide, and 750 mg of sodium hydride (60% strength suspensionin paraffin oil) are added. After 30 minutes, 6.7 g of4-iodomethyl-5-methyl-2-(3-methylphenyl)oxazole, dissolved in 20 ml ofdimethylformamide, are added dropwise. The mixture is stirred at roomtemperature for 1 hour. 200 ml of methy tert-buthyl ether are then addedto the reaction mixture, and the mixture is washed three times withwater. The organic phase is dried over magnesium sulfate and the solventis then removed under reduced pressure. The residue is purified byRP-HPLC. This gives 1.56 g of4-(cis-3-allylcyclohexyloxymethyl)-2-(3-methylphenyl)-5-methyloxazole asan oil. C₂₁H₂₇NO₂ (325.45), MS (ESI): 326 (M+H⁺),R_(f)(n-heptane:ethylacetate=2:1)=0.28.

{cis-3-[2-(3-Methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}-acetaldehyde

[0409]

[0410] 940 mg of4-(cis-3-allylcyclohexyloxymethyl)-2-(3-methylphenyl)-5-methyloxazoleare dissolved in 50 ml of diethyl ether, and 1.86 g of sodium periodate,dissolved in 50 ml of water, are added. At 0° C., 3 ml of an osmiumtetroxide solution (2.5% by weight in tert-butanol) are added, and themixture is stirred vigorously at room temperature. After 8 hours, 100 mlof methyl tert-butyl ether are added and the mixture is washed with asaturated sodium thiosulfate solution. The organic phase is dried overmagnesium sulfate and the solvent is then removed under reducedpressure. The residue is purified on silica gel using the mobile phasen-heptane:ethyl acetate=4:1. This gives 270 mg of{cis-3-[2-(3-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}acetaldehydeas a yellow-brown oil.

[0411] C₂₀H₂₅NO₃ (327.43), MS (ESI): 328 (M+H⁺),R_(f)(n-heptane:ethylacetate=2:1)=0.07.

5-{1-Hydroxy-2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]-ethyl}thiazolidine-2,4-dione

[0412]

[0413] 214 mg of thiazolidinedione are dissolved in 20 ml oftetrahydrofuran and, at −78° C., 1.4 ml of a 2.7 M solution ofn-butyllithium in n-hexane are added. The mixture is stirred at −78° C.for 30 minutes, and 500 mg of{cis-3-[2-(3-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}acetaldehyde,dissolved in 10 ml of tetrahydrofuran, are then added. After 30 minutesof stirring at −78° C., the mixture is allowed to warm to roomtemperature. 20 ml of 1N hydrochloric acid are added and the mixture isextracted three times with in each case 50 ml of ethyl acetate. Thecombined organic phases are dried over magnesium sulfate and the solventis then removed under reduced pressure. The residue is purified byRP-HPLC. This gives 420 mg of5-{1-hydroxy-2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dioneas a white solid. C₂₃H₂₈N₂O₅S (444.45), MS (ESI): 445 (M+H⁺)

EXAMPLE XXIX5-(1-Hydroxy-2-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0414] Analogously to Example XXVIII,{cis-3-[2-(3-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}acetaldehydeand thiazolididione give the compound5-(1-hydroxy-2-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0415] C₂₃H₂₈N₂O₆S (460.55), MS (ESI): 461 (M+H⁺).

EXAMPLE XXX5-{1-Hydroxy-2-[cis-3-(5-methyl-p-tolyloxazol-4-ylmethoxy)-cyclohexyl]-ethyl}thiazolidine-2,4-dione

[0416] Analogously to Example XXVIII,cis-[3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]acetaldehyde andthiazolididione gave the compound5-{1-hydroxy-2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]-ethyl}thiazolidine-2,4-dione.

[0417] C₂₃H₂₈N₂O₅S (444.55), MS (ESI): 445 (M+H⁺).

EXAMPLE XXXI5-{2-[cis-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}-thiazolidine-2,4-dione

[0418]

5-{2-[cis-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethylidene}-thiazolidine-2,4-dione.

[0419]

[0420] 344 mg of5-{1-hydroxy-2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dioneare dissolved in 20 ml of dichloromethane, and 0.13 ml of triethylamineand and 0.12 ml of mesyl chloride are added. The mixture is stirred atroom temperature for two hours, and another 0.13 ml of triethylamine andand 0.12 ml of mesyl chloride are added. The mixture is stirred at roomtemperature for 12 hours. 100 ml of dichloromethane are added, themixture is washed with saturated sodium bicarbonate solution and driedover magnesium sulfate and the solvent is then removed under reducedpressure. The resulting residue is dissolved in 10 ml of tetrahydrofuranand, at −78° C., 0.22 ml of a 2.7 M solution of n-butyllithium inn-hexane is added. The mixture is stirred at 0° C. for 30 minutes, 20 mlof 1N hydrochloric acid are then added and the mixture is extractedthree times with in each case 50 ml of ethyl acetate. The combinedorganic phases are dried over magnesium sulfate and the solvent is thenremoved under reduced pressure. The residue is purified by RP-HPLC. Thisgives 81 mg of5-{2-[Cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethylidene}thiazolidine-2,4-dioneas a white solid.

[0421] C₂₃H₂₆N₂O₄S (426.54), MS (ESI): 427 (M+H⁺).

5-{2-[cis-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}-thiazolidine-2,4-dione

[0422]

[0423] 81 mg of5-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]-ethylidene}thiazolidine-2,4-dioneare dissolved in 10 ml of ethyl acetate, and 10 mg of paladium (10% onactivated carbon) are added. The mixture is stirred under an atmosphereof hydrogen (5 bar) for 9 hours. The catalyst is then filtered offthrough Celite and the filtrate is concentrated under reduced pressure.The residue is purified by RP-HPLC. This gives 60 mg of5-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]-ethyl}thiazolidine-2,4-dioneas a lyophilisate.

[0424] C₂₃H₂₈N₂O₄S (428.55), MS (ESI): 429 (M+H⁺).

EXAMPLE XXXII5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}-ethyl)thiazolidine-2,4-dione

[0425] Analogously to Example XXXI,5-(1-hydroxy-2-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dionegave the compound5-(2-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione

[0426] C₂₃H₂₈N₂O₅S (444.55), MS (ESI): 445 (M+H⁺).

EXAMPLE XXXIII5-{2-[cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy]cyclohexyl]ethyl}-thiazolidine-2,4-dione

[0427] Analogously to Example XXXI,5-{1-hydroxy-2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dionegave the compound5-{2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dione.

[0428] C₂₃H₂₈N₂O₄S (428.55), MS (ESI): 429 (M+H⁺).

EXAMPLE XXXIV

[0429]5-[1-[cis-3-(5-Methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyl]methylidene]-thiazolidine-2,4-dione

cis-3-Hydroxymethylcyclohexanol

[0430]

[0431] 10 g of 6-oxabicyclo[3.2.1]octan-7-one are dissolved in 300 ml oftetrahydrofuran, and 160 ml of a 1 M solution of lithium aluminumhydride in tetrahydrofuran are added with ice-cooling. After 30 minutesof stirring at room temperature, a saturated ammonium chloride solutionis added and the pH is adjusted to neutral by addition of a 5% strengthcitric acid solution. The tetrahydrofuran is removed under reducedpressure and the residue is extracted three times with in each case 150ml of ethyl acetate. The combined organic phases are dried overmagnesium sulfate and the solvent is then removed under reducedpressure. This gives 10.5 g of cis-3-hydroxymethylcyclohexanol as acolorless oil. C₇H₁₄O₂ (130.13), Rf(ethyl acetate)=0.14.

cis-3-(tert-Butyl-diphenyl-silanyloxymethyl)cyclohexanol

[0432]

[0433] 10.5 g of cis-3-hydroxymethylcyclohexanol are dissolved in 300 mlof dimethylformamide, and 23 ml of tert-butyl-diphenyl-silanyl chloride,8.0 g of imidazole and 200 mg of dimethylaminopyridine are added. Themixture is stirred at room temperature for 12 hours. Thedimethylformamide is removed under reduced pressure and the residue isdissolved in 300 ml of ethyl acetate and washed five times with in eachcase 100 ml of water. The organic phase is dried over magnesium sulfateand the solvent is then removed under reduced pressure. This gives 27.0g of cis-3-(tert-butyl-diphenyl-silanyloxymethyl)cyclohexanol as an oil.C₂₃H₃₂O₂Si (368.6), Rf(n-heptane:ethyl acetate=1:1)=0.42.

cis-3-(tert-Butyl-diphenyl-silanyloxymethyl)cyclohexyloxymethyl]-5-methyl-2-p-tolyloxazole

[0434]

[0435] 6.4 g of cis-3-(tert-butyl-diphenyl-silanyloxymethyl)cyclohexanoland 6.5 g of 4-iodomethyl-5-methyl-2-p-tolyloxazole are dissolved in 200ml of dimethylformamide, and 1 g of sodium hydride (60% strengthsuspension in mineral oil) is added. After 1 hour of stirring at roomtemperature, another 2 g of sodium hydride and 5 g of4-iodomethyl-5-methyl-2-p-tolyloxazole are added. After 4 hours ofstirring at room temperature, the reaction mixture is diluted byaddition of 400 ml of ethyl acetate and washed five times with in eachcase 200 ml of water. The organic phase phase is dried over magnesiumsulfate and the solvent is then removed under reduced pressure. Theresidue is purified on silica gel using the mobile phase n-heptane:ethylacetate=10:1. This gives 6.8 g of4-cis-3-(tert-butyl-diphenyl-silanyloxymethyl)cyclohexyloxymethyl]-5-methyl-2-p-tolyloxazoleas an oil. C₃₅H₄₃NO₃Si (553.28), Rf(n-heptane:ethyl acetate=2:1)=0.50.

[(cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]methanol

[0436]

[0437] 6.8 g of4-cis-3-(tert-butyl-diphenyl-silanyloxymethyl)cyclohexyloxymethyl]-5-methyl-2-p-tolyloxazoleare dissolved in 40 ml of tetrahydrofuran, and 40 ml of a 1M solution oftetrabutylammonium fluoride are added. The mixture is heated at 50° C.for 1 hour and the solvent is then removed under reduced pressure andthe resulting residue is purified on silica gel using the mobile phasen-heptane:ethyl acetate=5:1≧1:1. This gives 1.0 g ofcis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]methanol as anoil. C19H25NO3 (315.42), Rf(n-heptane:ethyl acetate=1:1)=0.13.

cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarbaldehyde

[0438]

[0439] At −78° C., 0.89 ml of DMSO in 1 ml of dichloromethane is addeddropwise to 0.48 ml of oxalyl chloride in 15 ml of dichloromethane suchthat the temperature does not exceed −70° C. After the addition hasended, the solution is stirred at this temperature for 30 minutes. 1.5 gof cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]methanol in 2ml of dichloromethane are then added dropwise such that the temperatureremains below −78° C. The solution is stirred at this temperature for 30minutes. 3.2 ml of triethylamine are then added dropwise, the coolingbath is removed and the solution is warmed to 0° C. At this temperature,10 ml of water are added and the mixture is stirred vigorously at roomtemperature. The aqueous phase is removed and extracted withdichloromethane. The combined organic phases are washed with saturatedammonium chloride solution, dried over magnesium sulfate andconcentrated, which gives 1.50 g ofcis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarbalde-hyde.C₁₉H₂₃NO₃ (313.40), LCMS (ESI): 314 (MH⁺).

5-[1-[cis-3-(5-Methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyl]-methylidene]thiazolidine-2,4-dione

[0440]

[0441] 0.25 g of thiazolidinedione are initially charged in athree-necked flask, which had been dried by heating, dissolved in 15 mlof tetrahydrofuran and cooled to −78° C., and 2.4 ml of n-buthyllithium(1.6 M solution in n-hexane) are slowly added dropwise such that theinternal temperature does not exceed −65° C. The solution is then warmedto room temperature, resulting in the color of the solution changing toyellow. The mixture is again cooled to −70° C., and 0.4 g ofcis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarbaldehyde—dissolvedin 5 ml of tetrahydrofuran—is then added dropwise, and the reactionmixture is warmed to room temperature. The tertiary alcohol is formed asan adduct (reaction control (TLC and LCMS) M=430 g/mol). Acidic work-up(5 ml 1 N HCl) and extraction with 2×10 ml of ethyl acetate gives thedesired elimination product after removal of the solvent under reducedpressure. The crude product is taken up in acetonitrile and the motherliquor is filtered off, giving 0.5 g of5-[1-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyl]-methylidene]thiazolidine-2,4-dioneas a white solid.

[0442] C₂₂H₂₄N₂O₄S (412.54), MS (ESI): 413 (M+H⁺).

EXAMPLE XXXV5-[cis-3-(5-Methyl-2-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]thiazolidine-2,4-dione

[0443] The compound5-[1-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyl]-methylidene]thiazolidine-2,4-dione,mentioned in Example XXXIV, is obtained by hydrogenation of the compound5-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]thiazolidine-2,4-dione.

[0444] 0.35 g of5-[1-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyl]-methylidene]thiazolidine-2,4-dioneis dissolved in 12 ml of a solvent mixture of ethyl acetate and methanol(3:1), and 20 mg of palladium-on-carbon are added. The mixture is thenhydrogenated at room temperature under a hydrogen pressure of 3 bar for2 hours. The catalyst is filtered off and the solvent is then removedunder reduced pressure and the residue is taken up in acetonitrile. Theproduct can be filtered off, giving 0.3 g of5-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]thiazolidine-2,4-dioneas a white solid. C₂₂H₂₆N₂O₄S (414.52), MS (ESI): 415 (M+H⁺).

EXAMPLE XXXVI5-(2-{(cis-3-[5-cyclohexyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0445] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-cyclohexyl-2-(3-methoxyphenyl)oxazole gave the compound5-(2-{(cis-3-[5-cyclohexyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0446] C28H36N2O5S (512.67), MS(ESI): 513 (M+H⁺)

EXAMPLE XXXVII5-(2-{(cis-3-[5-cyclohexyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0447] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-cyclohexyl-2-(4-methylphenyl)oxazole gave the compound5-(2-{(cis-3-[5-cyclohexyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0448] C28H36N2O4S (496.67), MS(ESI): 497 (M+H⁺).

EXAMPLE XXXVIII5-(2-{(cis-3-[5-ethyl-2-(3,5-bis-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0449] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(3,5-bis-trifluoromethylphenyl)-oxazole gave thecompound5-(2-{(cis-3-[5-ethyl-2-(3,5-bis-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0450] C25H26F6N2O4S (564.55), MS(ESI): 565 (M+H⁺)

EXAMPLE XXXIX5-(2-{(cis-3-[5-ethyl-2-(2,6-bis-dimethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0451] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(2,6-dimethylphenyl)oxazole gave the compound5-(2-{(cis-3-[5-ethyl-2-(2,6-dimethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0452] C25H32N2O4S (456.64), MS(ESI): 457 (M+H⁺).

EXAMPLE XL5-(2-{(cis-3-[5-methyl-2-(2-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0453] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-methyl-2-(2-trifluoromethylphenyl)oxazole gave thecompound5-(2-{(cis-3-[5-methyl-2-(2-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0454] C23H25F3N2O4S (482.53), MS(ESI): 483 (M+H⁺).

EXAMPLE XLI5-(2-{(cis-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0455] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(3-methoxyphenyl)oxazole gave the compound5-(2-{(cis-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0456] C24H30N2O5S (458.58), MS(ESI): 459 (M+H⁺).

EXAMPLE XLII5-(2-{(cis-3-[5-ethyl-2-(2-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0457] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(2-trifluorophenyl)oxazole gave the compound5-(2-{(cis-3-[5-ethyl-2-(2-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0458] C24H27F3N2O4S (496.55), MS(ESI): 497 (M+H⁺).

EXAMPLE XLIII5-{2-[3-(5-ethyl-2-p-tolyloxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione

[0459] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(4-methylphenyl)oxazole gave the compound5-{2-[cis-3-(5-ethyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}-thiazolidine-2,4-dione.

[0460] C24H30N2O4S (442.58), MS(ESI): 443 (M+H⁺).

EXAMPLE XLIV5-(2-{(cis-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0461] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(4-isopropylphenyl)oxazole gave the compound5-(2-{cis-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0462] C26H34N2O4S (470.64), MS(ESI): 471 (M+H⁺).

EXAMPLE XLV5-(2-{(cis-3-[5-isopropyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0463] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(4-isopropylphenyl)oxazole gave the compound5-(2-{cis-3-[5-isopropyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0464] C25H32N2O4S (456.61), MS(ESI): 457 (M+H⁺).

EXAMPLE XLVI5-(2-{(cis-3-[5-methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0465] Analogously to Example XXVIII and Example XXXI,cis-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-methyl-2-(3-trifluoromethylphenyl)oxazole gave thecompound5-(2-{(cis-3-[5-methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0466] C23H25F3N2O4S (482.53), MS(ESI): 483 (M+H⁺).

EXAMPLE XLVII

[0467] The compound5-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethylidene}thiazolidine-2,4-dionefrom Example XXXI was separated by chromatography on a chiral phase intothe compounds5-{2-[(1S,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethylidene}thiazolidine-2,4-dioneand5-{2-[(1R,3R)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethylidene}thiazolidine-2,4-dione.

5-{2-[(1R,3R)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]-ethylidene}thiazolidine-2,4-dione:

[0468]

[0469] C₂₃H₂₈N₂O₄S (428.55), MS(ESI): 429 (M+H⁺).

5-{2-[(1S,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]-ethylidene}thiazolidine-2,4-dione:

[0470]

[0471] C₂₃H₂₈N₂O₄S (428.55), MS(ESI): 429 (M+H⁺).

EXAMPLE XLVIII

[0472] The compound5-(2-{cis-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dionefrom Example XLIV was separated by chromatography on a chiral phase intothe compounds5-(2-{(1s,3S)-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dioneand5-(2-{(1R,3R)-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

5-(2-{(1s,3S)-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione:

[0473]

[0474] C26H34N2O4S (470.64), MS(ESI): 471 (M+H⁺).

5-(2-{(1R,3R)-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione:

[0475]

[0476] C26H34N2O4S (470.64), MS(ESI): 471 (M+H⁺).

EXAMPLE XLIX

[0477] The compound5-{2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dionefrom Example XXXIII was separated by chromatography on a chiral phaseinto the compounds5-{2-[(1S,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dioneand5-{2-[(1R,3R)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dione.

5-{2-[(1S,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}-thiazolidine-2,4-dione

[0478]

[0479] C₂₃H₂₈N₂O₄S (428.55), MS(ESI): 429 (M+H⁺).

5-{2-[(1R,3R)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}-thiazolidine-2,4-dione

[0480]

[0481] C₂₃H₂₈N₂O₄S (428.55), MS(ESI): 429 (M+H⁺).

EXAMPLE L5-(2-{(1S,3S)-3-[2-(3,4-dimethylphenyl)-5-ethyloxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione((1S,3S)-3-allylcyclohexanol

[0482]

[0483] 50 g of cis-3-allylcyclohexanol are dissolved in 200 ml vinylacetate, and 3 g of lipase (Novozym) added. The mixture is stirred at RTuntil a conversion of 58% is reached (the conversion is monitored byGC). The enzyme is filtered off and the vinyl acetate is removed underreduced pressure. The resulting residue is purified chromatographicallyon silica gel. This gives 17 g of (1S, 3S)-3-allylcyclohexanol as acolorless oil.

[0484] C8H14O (126.20), Rf (n-heptane:ethyl acetate=1:1)=0.46.

5-(2-{(1S,3S)-3-[2-(3,4-dimethylphenyl)-5-ethyloxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione

[0485] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(3,4-dimethylphenyl)oxazol gave the compound5-(2-{(1S,3S)-3-[2-(3,4-dimethylphenyl)-5-ethyloxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione

[0486] C₂₅H₃₂N₂O₄S (456.61), MS(ESI): 457 (M+H⁺).

EXAMPLE LI5-(2-{(1S,3S)-3-[5-Ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0487] Analogously to Example XXVIII and Example XXXI,(1S,3S)-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(4-trifluoromethylphenyl)oxazole gave thecompound5-(2-{(1S,3S)-3-[5-ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0488] C24H27F3N2O4S (496.55), MS(ESI): 497 (M+H⁺).

EXAMPLE LII5-{2-[(1S,3S)-3-(5-Ethyl-2-naphthalen-2-yl-oxazol-4-ylmethoxy)cyclohexyl]ethyl}-thiazolidine-2,4-dione

[0489] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allyl-cyclohexanol, thiazolidinedione and5-ethyl-4-iodomethyl-2-naphthalen-2-yloxazole gave the compound5-{2-[(1S,3S)-3-(5-ethyl-2-naphthalen-2-yloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dione.

[0490] C27H30N2O4S (478.62), MS(ESI): 479 (M+H⁺).

EXAMPLE LIII5-(2-{(1S,3S)-3-[5-Ethyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0491] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(3-trifluoromethylphenyl)oxazole gave thecompound5-(2-{(1S,3S)-3-[5-ethyl-2-(3-trifluoromethylphenyl)-oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0492] C24H27F3N2O4S (496.55), MS(ESI): 497 (M+H⁺).

BEISPIEL LIV5-(2-{(1S,3S)-3-[5-Ethyl-2-(4-tert-butylphenyl)oxazol-4-ylmethoxy]cyclohexyl}-ethyl)thiazolidine-2,4-dione

[0493] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(4-tert-butylphenyl)oxazole gave the compound5-(2-{(1S,3S)-3-[5-ethyl-2-(4-tert-butylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0494] C27H36N2O4S (484.66), MS(ESI): 485 (M+H⁺).

EXAMPLE LV5-(2-{(1S,3S)-3-[5-Isopropyl-2-(3,4-dimethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0495] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-isopropyl-2-(3,4-dimethylphenyl)oxazole gave the compound5-(2-{(1S,3S)-3-[5-isopropyl-2-(3,4-dimethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0496] C26H34N2O4S (470.64), MS(ESI): 471 (M+H⁺).

EXAMPLE LVI5-(2-{(1S,3S)-3-[5-Ethyl-2-(4-isobutylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)-thiazolidine-2,4-dione

[0497] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-ethyl-2-(4-isobutylphenyl)oxazole gave the compound5-(2-{(1S,3S)-3-[5-ethyl-2-(4-isobutylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidin-2,4-dione.

[0498] C27H36N2O4S (484.66), MS(ESI): 485 (M+H⁺).

EXAMPLE LVII5-(2-{(1S,3S)-3-[5-Isopropyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0499] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-isopropyl-2-(3-trifluormethylphenyl)oxazole gave thecompound5-(2-{(1S,3S)-3-[5-isopropyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0500] C25H29F3N2O4S (510.58), MS(ESI): 511 (M+H⁺).

EXAMPLE LVIII5-(2-{(1S,3S)-3-[5-Isopropyl-2-(4-tert-butylphenyl)oxazol-4-ylmethoxy]cyclohexyl}-ethyl)thiazolidine-2,4-dione

[0501] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-isopropyl-2-(4-tert-butylphenyl)oxazol gave the followingcompound5-(2-{(1S,3S)-3-[5-isopropyl-2-(4-tert-butylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0502] C28H38N2O4S (498.69), MS(ESI): 499 (M+H⁺).

EXAMPLE LIX5-(2-{(1S,3S)-3-[5-Isopropyl-2-(4-isobutylphenyl)oxazol-4-ylmethoxy]cyclohexyl}-ethyl)thiazolidine-2,4-dione

[0503] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-isopropyl-2-(4-isobutylphenyl)oxazole gave the compound5-(2-{(1S,3S)-3-[5-isopropyl-2-(4-isobutylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0504] C28H38N2O4S (498.69), MS(ESI): 499 (M+H⁺).

EXAMPLE LX5-(2-{(1S,3S)-3-[5-Isopropyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

[0505] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allylcyclohexanol, thiazolidinedione and4-iodomethyl-5-isopropyl-2-(4-trifluoromethylphenyl)oxazole gave thecompound5-(2-{(1S,3S)-3-[5-isopropyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

[0506] C25H29F3N2O4S (510.58), MS(ESI): 511 (M+H⁺).

EXAMPLE LXI5-{2-[(1S,3S)-3-(5-Isopropyl-2-naphthalen-2-yloxazol-4-ylmethoxy)cyclohexyl]-ethyl}thiazolidine-2,4-dione

[0507] Analogously to Example XXVIII and Example XXXI(1S,3S)-3-allylcyclohexanol, thiazolidinedione and5-isopropyl-4-iodomethyl-2-naphthalen-2-yloxazole gave the compound5-{2-[(1S,3S)-3-(5-isopropyl-2-naphthalen-2-yloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dione.

[0508] C28H32N2O4S (492.64), MS(ESI): 493 (M+H⁺).

EXAMPLE LXII5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione

[0509] Analogously to Example XXVIII and Example XXXIcis-3-allylcyclohexanol, 3-methylthiazolidinedione and4-iodomethyl-5-methyl-2-(3-methoxyphenyl)oxazole gave the compound5-(2-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione.

[0510] C24H30N2O5S (458.58), MS(ESI): 459 (M+H⁺).

BEISPIEL LXIII5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-phenylthiazolidine-2,4-dione

[0511] Analogously to Example XXVIII and Example XXXIcis-3-allylcyclohexanol, 3-phenylthiazolidinedione and4-iodomethyl-5-methyl-2-(3-methoxyphenyl)oxazole gave the compound5-(2-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-phenylthiazolidine-2,4-dione.

[0512] C29H32N2O5S (520.65), MS(ESI): 521 (M+H⁺).

EXAMPLE LXIV5-(2-{cis-3-[2-(4-Methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione

[0513] Analogously to Example XXVIII and Example XXXIcis-3-allylcyclohexanol, 3-methylthiazolidinedione and4-iodomethyl-5-methyl-2-(4-methylphenyl)oxazole gave the compound5-(2-{cis-3-[2-(4-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione.

[0514] C24H30N2O4S (442.58), MS(ESI): 443 (M+H⁺).

EXAMPLE LXV5-(2-{cis-3-[2-(4-Methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-benzylthiazolidine-2,4-dione

[0515] Analogously to Example XXVIII and Example XXXIcis-3-allylcyclohexanol, 3-benzylthiazolidinedione and4-iodomethyl-5-methyl-2-(4-methylphenyl)oxazole gave the compound5-(2-{cis-3-[2-(4-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-benzylthiazolidine-2,4-dione.

[0516] C30H34N2O4S (518.58), MS(ESI): 519 (M+H⁺).

EXAMPLE LXVI5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-isopropyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione

[0517] Analogously to Example XXVIII and Example XXXIcis-3-allylcyclohexanol, 3-methylthiazolidinedione and4-iodomethyl-5-isopropyl-2-(3-methoxyphenyl)-oxazole gave the compound5-(2-{cis-3-[2-(3-methoxyphenyl)-5-isopropyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione.

[0518] C26H34N2O5S (486.64), MS(ESI): 487 (M+H⁺).

EXAMPLE LXVII5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-phenyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione

[0519] Analogously to Example XXVIII and Example XXXIcis-3-allylcyclohexanol, 3-methylthiazolidinedione and4-iodomethyl-5-phenyl-2-(3-methoxyphenyl)oxazole gave the compound5-(2-{cis-3-[2-(3-methoxyphenyl)-5-phenyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione.

[0520] C29H32N2O5S (520.65), MS(ESI): 521 (M+H⁺).

EXAMPLE LXVIII5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-phenyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-phenylthiazolidine-2,4-dione

[0521] Analogously to Example XXVIII and Example XXXIcis-3-allylcyclohexanol, 3-phenylthiazolidinedione and4-iodomethyl-5-phenyl-2-(3-methoxyphenyl)oxazole gave the compound5-(2-{cis-3-[2-(3-methoxyphenyl)-5-phenyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-phenylthiazolidine-2,4-dione.

[0522] C34H34N2O5S (582.72), MS(ESI): 583 (M+H⁺).

1 2 1 19 DNA Artificial Binding Site of Yeast Transcription Factor GAL41 cggagtactg tcctccgag 19 2 19 DNA Artificial Binding Site of YeastTranscription Factor GAL4 2 ctcggaggac agtactccg 19

We claim:
 1. A compound of the formula I

wherein Ring A is (C₃-C₈)-cycloalkanediyl or (C₃-C₈)-cycloalkenediyl,wherein one or more of the carbon atoms of said (C₃-C₈)-cycloalkanediyland (C₃-C₈)-cycloalkenediyl groups are optionally replaced by an oxygenatom; R₁, R₂ are each independently H, F, Br, CF₃, OCF₃, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, SCF₃, SF₅, OCF₂—CHF₂, O-phenyl, OH, or NO₂; or R₁, andR₂, taken together with the carbon atoms of the phenyl ring to whichthey are attached, form a fused, unsaturated or completely or partiallysaturated bicyclic (C₉-C₁₂)-aryl or (C₉-C₁₁)-heteroaryl ring system; R3is H, CF₃, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₃-C₈)-cycloalkyl or phenyl;x is (C₁-C₆)-alkanediyl, wherein one or more carbon atoms therein isoptionally replaced by an oxygen atom; Y is (C₁-C₆)-alkanediyl or(C₁-C₆)-alkenediyl, wherein one or more carbon atoms therein isoptionally replaced by O, CO, S, SO or SO₂, and wherein said(C₁-C₆)-alkanediyl and (C₁-C₆)-alkenediyl groups are optionallysubstituted by OH; Ring B is a group selected from (a), (b) or (c): (a)phenyl optionally mono- or disubstituted by NO₂, Cl, CN, (C₁-C₆)-alkylor (C₁-C₆)-alkoxy (b) tetrazole (c) pyrrolidin-2-one wherein thepyrrolidinyl ring of said pyrrolidin-2-one group contains an additionalnitrogen atom or a sulfur atom and is substituted by oxo or thioxo, andis optionally substituted on a nitrogen atom therein by R4; R4 is(C₁-C₆)-alkyl, phenyl or benzyl; and pharmaceutically acceptable saltsthereof.
 2. The compound of claim 1 wherein: Ring A is(C₃-C₈)-cycloalkanediyl or (C₃-C₈)-cycloalkenediyl, wherein one of thecarbon atoms of said (C₃-C₈)-cycloalkanediyl and (C₃-C₈)-cycloalkenediylgroups is optionally replaced by an oxygen atom; R1, R2 are eachindependently H, F, Br, CF₃, OCF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, SCF₃,SF₅, OCF₂—CHF₂, O-phenyl, OH or NO₂; or R₁ and R₂, taken together withthe carbon-atoms of the phenyl ring to which they are attached, form afused, unsaturated or completely or partially saturated bicyclic(C₉-C₁₂)-aryl or (C₉-C₁₁)-heteroaryl ring system; R3 is H, CF₃,(C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl or phenyl; x is (C₁-C₆)-alkanediyl,wherein one carbon atom therein is optionally replaced by an oxygenatom; Y is (C₁-C₆)-alkanediyl or (C₁-C₆)-alkenediyl, wherein one or twocarbon atoms of said (C₁-C₆)-alkanediyl and (C₁-C₆)-alkenediyl groupsare optionally replaced by O, CO, S, SO or SO₂, and wherein said(C₁-C₆)-alkanediyl and (C₁-C₆)-alkenediyl groups are optionallysubstituted by OH; Ring B is a group selected from (a), (b) or (c): (a)phenyl optionally mono- or disubstituted by NO_(2, Cl, CN,)(C₁-C₆)-alkyl or (C₁-C₆)-alkoxy (b) tetrazole (c) pyrrolidin-2-onewherein the pyrrolidinyl ring of said pyrrolidin-2-one group contains anadditional nitrogen atom or a sulfur atom in the 4-position and issubstituted by oxo or thioxo in the 5-position, and is optionallysubstituted on the nitrogen atom in the 1-position by R4; R4 is(C₁-C₆)-alkyl, phenyl or benzyl; and pharmaceutically acceptable saltsthereof.
 3. The compound of claim 2 wherein: Ring A is(C₃-C₈)-cycloalkanediyl wherein one carbon atom therein is replaced byan oxygen atom; R₁, R₂ are each independently H, F, Br, CF₃, OCF₃,(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, SCF₃, SF₅, OCF₂—CHF₂, O-phenyl, OH orNO₂; or R₁ and R₂, taken together with the carbon atoms of the phenylring to which they are attached, form a fused, unsaturated or completelyor partially saturated bicyclic (C₉-C₁₂)-aryl or (C₉-C₁₁)-heteroarylring system; R3 is H, CF₃, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl or phenyl;X is (C₁-C₆)-alkanediyl, wherein the carbon atom in the 1-position isreplaced by an oxygen atom; Y is (C₁-C₆)-alkanediyl or(C₁-C₆)-alkenediyl, wherein one or two carbon atoms of said(C₁-C₆)-alkanediyl and (C₁-C₆)-alkenediyl groups are optionally replacedby O, CO or SO₂, and wherein said (C₁-C₆)-alkanediyl and(C₁-C₆)-alkenediyl groups are optionally substituted by OH; Ring B is agroup selected from (a), (b) or (c): (a) phenyl optionally mono- ordisubstituted by NO_(2, Cl, CN,) (C₁-C₆)-alkyl or (C₁-C₆)-alkoxy (b)tetrazole (c) pyrrolidin-2-one wherein the pyrrolidinyl ring of saidpyrrolidin-2-one group contains an additional nitrogen atom or a sulfuratom in the 4-position and is substituted by oxo or thioxo in the5-position, and is optionally substituted on the nitrogen atom in the1-position by R4; R4 is (C₁-C₆)-alkyl, phenyl or benzyl; andpharmaceutically acceptable salts thereof.
 4. The compound of claim 3wherein: Ring A is cyclohexane-1,3-diyl; R₁, R₂ are each independentlyH, F, Br, CF₃, OCF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, SCF₃, SF₅,OCF₂—CHF₂, O-phenyl, OH or NO₂; or R1 and R2, taken together with thecarbon atoms of the phenyl ring to which they are attached, form afused, unsaturated bicyclic (C₉-C₁₀)-aryl or (C₉-C₁₀)-heteroaryl ringsystem; R3 is H, CF₃, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl or phenyl; x isCH₂—O; Y is (C₁-C₄)-alkanediyl, O—(C₁-C₄)-alkenediyl,(C₁-C₄)-alkenediyl, O—(C₁-C₄)-alkenediyl, O—SO₂ or O—CO, wherein said(C₁-C₄)-alkanediyl group is optionally substituted by OH; Ring B is agroup selected from (a), (b) or (c): (a) phenyl optionally mono- ordisubstituted by NO_(2, Cl, CN,) (C₁-C₆)-alkyl or (C₁-C₆)-alkoxy (b)tetrazole (c) thiazolidin-1,4-dione optionally substituted by R4 on thenitrogen in the 3-position-atom; R4 is (C₁-C₆)-alkyl, phenyl or benzyl;and pharmaceutically acceptable salts thereof.
 5. The compound of claim4 wherein: Ring A is cyclohexane-1,3-diyl; R₁, R₂ are each independentlyH, F, Br, CF₃, (C₁-C₆)-alkyl or O—(C₁-C₆)-alkyl; or R₁ and R₂, takentogether with the carbon atoms of the phenyl ring to which they areattached, form naphthyl; R3 is (C₁-C₆)-alkyl, (C₅-C₆)-cycloalkyl orphenyl; X is CH₂—O; Y is (C₁-C₄)-alkanediyl, O—(C₁-C₄)-alkanediyl,(C₁-C₄)-alkenediyl, O—(C₁-C₄)-alkenediyl, O—SO₂ or O—CO, where said(C₁-C₄)-alkanediyl group is optionally substituted by OH; Ring B is agroup selected from (a), (b) or (c): (a) phenyl optionally mono- ordisubstituted by NO_(2, Cl, CN,) (C₁-C₆)-alkyl or (C₁-C₆)-alkoxy (b)tetrazole (c) thiazolidin-2,4-dione optionally substituted by R4 on thenitrogen in the 3-position; R4 is (C₁-C₆)-alkyl, phenyl or benzyl; andpharmaceutically acceptable salts thereof.
 6. The compound of claim 5wherein: R2 is hydrogen; and R1 is attached to the carbon of the phenylring that is meta- or para- to the carbon by which the phenyl ring isattached to the oxazole ring.
 7. The compound of claim 6 wherein: Y is—CH₂—CH₂—.
 8. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and one or more compounds of claim
 1. 9. Thepharmaceutical composition of claim 8 further comprising at least oneadditional active ingredient.
 10. The pharmaceutical composition ofclaim 9 wherein said additional active ingredient has favorable effectson metabolic disturbances or disorders.
 11. The pharmaceuticalcomposition of claim 9 wherein said additional active ingredient is anantidiabetic.
 12. The pharmaceutical composition of claim 9 wherein saidadditional active ingredient is a lipid modulator.
 13. A method oftreating disorders of fatty acid metabolism and glucose utilizationcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 14. A method of treatingdisorders of insulin resistence comprising administering to a patient inneed thereof a therapeutically effective amount of a compound ofclaim
 1. 15. A method of treating diabetes mellitus including theprevention of the squelae associated therewith comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of claim
 1. 16. A method of treating dyslipidemia and squelaeassociated therewith comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim
 1. 17.A method of treating metabolic syndrome and conditions associatedtherewith comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim
 1. 18. A methodof treating disorders of fatty acid metabolism and glucose utilizationcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim 1 in combination with at leastone further active compound.
 19. A method of treating disorders ofinsulin resistance comprising administering to a patient in need thereofa therapeutically effective amount of a compound of claim 1 incombination with at least one further active compound.